85898 NUMS Journal - Robert H. Lurie Comprehensive Cancer

Transcription

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CONTENTS
Spring-Summer 2004
Volume IX, Number 2
2
Letter from the Editor
4
Notable Cancer Center Member
Leo I. Gordon, MD
6
Leonidas C. Platanias, MD, PhD
9
Investigating the Possible Effects of
Tomatoes or Lycopene in Preventing
Prostate Cancer
Peter H. Gann, MD, ScD, Susie Lee, MPH,
Misop Han, MD, Ryan Deaton and
Vijayalakshmi Ananthanarayanan, MD
15 Four-Dimensional Elastic Light-Scattering
Fingerprinting for Early Detection of
Colon Carcinoginesis
Vadim Backman, PhD, Michael J. Goldberg,
MD, Young L. Kim, Yang Liu, Hemant K.
Roy, MD and Ramesh K. Wali, PhD
21 The Mechanism by which EBNA1 Supports
the Replication and Partitioning of Latent
EBV Genomes
Ashok Aiyar, PhD and John M. Sears
28 Filopodia Formation and Cancer
Metastasis
Gary Borisy, PhD and Danijela Vignjevic
35 Controlled Release Systems for
Non-Viral Vectors
EDITOR
EDITORIAL BOARD
Steven T. Rosen, MD, FACP
Director
Thomas Adrian, PhD
Hamid Band, MD, PhD
Richard Bell, MD
Charles L. Bennett, MD, PhD
Raymond Bergan, MD
William Catalona, MD
David Cella, PhD
Susan Gapstur, PhD
Ronald Gartenhaus, MD
V. Craig Jordan, OBE, PhD, DSc
Chung Lee, PhD
Richard Longnecker, PhD
Andreas Matouschek, PhD
Thomas V. O’Halloran, PhD
Elizabeth Perlman, MD
Gustavo Rodriguez, MD
M. Sharon Stack, PhD
Martin S. Tallman, MD
ASSOCIATE EDITOR
Leonidas Platanias, MD, PhD
Deputy Director
ASSOCIATE EDITOR
Leo I. Gordon, MD
Associate Director for
Clinical Sciences
ASSOCIATE EDITOR
Philip Greenland, MD
Associate Director for Cancer
Prevention and Control
ASSOCIATE EDITOR
Kathleen Rundell, PhD
Associate Director for Education
ASSISTANT EDITOR
ASSOCIATE EDITOR
Tim Volpe
Administration
Sharon Markman
Lonnie D. Shea, PhD and Angela K. Pannier
40 Quality of Life Impact of Early Radiation
Treatment for Breast Cancer
Deborah Dobrez, PhD, William Small, Jr., MD,
Matthew Callahan, BS, Krystyna Kiel, MD
and Emily Welshman, MSW
46 Shared Research Core Facilities
48 Selected Member Abstracts
June 2003 - December 2003
56 Selected Bibliography of Publications
by Cancer Center Members
70 Cancer Center Advisory Boards
72 Members Who Contributed to this Issue
MANAGING EDITOR
Ann Klimek
ASSOCIATE EDITOR
PHOTOGRAPHY
Teresa Woodruff, PhD
Basic Sciences
Jim Ziv
73 Cancer Center Education Programs
and Community Events
75 Cancer Center Affiliated Research
Facilities and Teaching Hospitals
©Northwestern University 2004
ISSN 1049-6025
The Journal of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Vol. IX
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Letter from the Editor
Steven T. Rosen, MD, FACP
T
he recruitment of established senior investigators can have a profound impact on
an institution. Over the course of the last three
years, the Robert H. Lurie Comprehensive
Cancer Center of Northwestern University
has been fortunate to welcome a number of
highly regarded clinicians and scientists to
our Cancer Center. These individuals are listed
by year with their previous institution, Cancer
Center program affiliation and research area.
2001
Thomas Adrian, PhD – Creighton Cancer
Center, Creighton School of Medicine;
Gastrointestinal Oncology Program;
Growth factors and intracellular signaling
in pancreatic cancer.
Martha Bohn, PhD – University of Rochester
Medical Center; Cancer Genes and Molecular
Regulation Program; Neurotrophic factors and
gene therapy for neurodegenerative diseases.
Richard Carthew, PhD – University of
Pittsburgh; Hormone Action and Signal
Transduction in Cancer Program; Molecular
mechanisms that receptor tyrosine kinases
use to regulate cell behavior.
2
Jayesh Mehta, MD – South Carolina Cancer
Center and Palmetto Richland Memorial
Hospital, University of South Carolina;
Hematologic Malignancies Program; Bone
marrow and stem cell transplantation.
Seema Singhal, MD – South Carolina Cancer
Center and Palmetto Richland Memorial
Hospital, University of South Carolina;
Hematologic Malignancies Program;
Plasma cell dyscrasias.
2002
Thomas Meade, PhD – California Institute
of Technology; Cancer Genes and Molecular
Regulation Program; Inorganic coordination
chemistry for the study of molecular imaging
in vivo gene expression.
Leonidas Platanias, MD, PhD – University of
Illinois at Chicago; Hematologic Malignancies
Program; Mechanisms of signal transduction of
interferons and other cytokines in malignant cells.
Gustavo Rodriguez, MD – Duke University
Medical Center; Gynecologic Oncology and
Hormone Action and Signal Transduction
Programs; Effective pharmacologic approach
for the prevention of ovarian cancer.
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Hemant Roy, MD – University of Nebraska
Medical Center; Gastrointestinal Oncology
and Hormone Action and Signal Transduction
Programs; Understanding the mechanisms by
which nonsteroidal anti-inflammatory drugs
prevent colorectal cancer.
Alexis Thompson, MD – UCLA Medical
School; Pediatric Oncology Program; Bone
marrow and stem cell transplantation in
pediatric patients.
2003
Hamid Band, MD, PhD – Harvard
Medical School; Hormone Action and Signal
Transduction Program; Define the role of
Cbl-family proteins.
Vimla Band, PhD – Tufts, New England
Medical Center; Breast Cancer and Viral
Oncogenesis Programs; Delineate the molecular
basis of early steps in human breast cancer.
Irina Budunova, MD, PhD – AMC Cancer
Research Center; Hormone Action and Signal
Transduction in Cancer Program; Mechanisms
of skin and prostate tumor genesis.
Serdar Bulun, MD – University of Illinois at
Chicago; Breast Cancer and Hormone Action
and Signal Transduction in Cancer Programs;
Mechanisms of estrogen biosynthesis and regulation of steroidogenic genes in human disease.
William Catalona, MD – Washington
University School of Medicine; Prostate Cancer
Program; PSA-based screening for prostate
cancer and the genetics of prostate cancer.
Richard Miller, PhD – University of Chicago;
Hormone Action and Signal Transduction
Program; Molecular neuroscience and receptor
signaling mechanisms.
Elizabeth Perlman, MD – John Hopkins
University School of Medicine; Pediatric
Oncology Program; Genetic expression analysis
of pediatric germ cell tumors.
Gayle Woloschak, PhD – Argonne National
Laboratory; Cancer Genes and Molecular
Program; Understanding molecular basis of
radiation responses in mammalian cells and
in radiosensitive mice.
2004
Edward Grendys, Jr., MD – University of
South Florida, School of Medicine; Gynecologic
Oncology Program; Clinical research protocols
involving ovarian, uterine and cervical cancer.
Mary Hendrix, PhD – University of Iowa;
Pediatric Oncology Program; Plasticity of
aggressive tumor cells and the epigenetic
influence of the microenvironment.
Olke Uhlenbeck, PhD – University of
Colorado; Cancer Genes and Molecular
Regulation Program; RNA biochemistry.
These individuals are already making important
contributions to our research programs. Their
presence elevates the image of our Cancer
Center and brings us great pride. They serve
as mentors to trainees, as role models for junior
faculty and as seasoned leaders advancing our
scientific agenda.
Paul Lindholm, MD – Medical College of
Wisconsin; Prostate Cancer Program; Signaling
and gene expression of cancer cells that regulate
their mobility, invasion and metastasis.
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Leo I. Gordon, MD
W
hen asked how he first became interested
in medicine, Leo I. Gordon, MD, credits
his family. The son of a physician and a nurse,
Dr. Gordon and his twin sister were steeped in
all things medical during their Chicago childhoods, so not surprisingly, both grew up to
be successful physicians themselves.
Indeed, for Dr. Gordon, the Abby and John
Friend Professor of Cancer Research and
Professor of Medicine at the Feinberg School
of Medicine at Northwestern University;
Chief, Division of Hematology/Oncology and
Associate Director for Clinical Sciences at the
Robert H. Lurie Comprehensive Cancer Center
of Northwestern University, medicine and the
study of blood diseases and cancer have been
a central focus.
After receiving his MD from the University
of Cincinnati and completing his internship
and residency at the University of Chicago,
Dr. Gordon continued studying through
fellowships at the University of Minnesota and
University of Chicago where, under the guidance of his mentor, the late John Ultmann,
MD, he began to concentrate on research,
particularly related to lymphomas. “I had a
strong attraction to this specialty, because the
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science is fascinating and it is readily translated
from the laboratory to the patient,” Dr. Gordon
says. Now he is a premier clinician-scientist,
nationally distinguished for his work in nonHodgkin’s lymphomas. He joined the faculty
of Northwestern in 1979 and became chief
of hematology/oncology in 1996.
His current interests lie in radioimmunotherapy
of lymphoma and free radical biology.
Radioimunotherapy is a revolutionary treatment
using antibodies to deliver radiation to the
tumors via I.V. injection, therefore targeting
the cancer sites more effectively and sparing the
patient the worst side effects linked with traditional radiation and chemotherapy. Free radical
biology involves the study of oxygen radicals or
reactive oxygen species, which are ubiquitous
because they are produced as a consequence
of our oxygen-rich environment. It appears that
these substances are important not only as
possible causes of certain cancers (an observation made by Dr. Sigmund Wietzman, also
a member of the Division of Hematology/
Oncology and former Division Chief), but
paradoxically may be necessary in order to
treat certain cancers. The study of our adapation to oxidant stress is a fundamental theme in
Dr. Gordon’s research. Dr. Gordon, along with
his colleagues Ron Gartenhaus, MD, Andrew
Evens, MD and Sheila Prachand, have been
examining cell lines in lymphoma and myeloma
in order to study the role of free radicals in cell
death pathways. Soon clinical studies of agents
which target cell components which generate
free radicals and promote death pathways in
cancer cells will be started. “We hope that this
approach will provide an effective, targeted
treatment for lymphoma and other cancers,”
says Dr. Gordon.
Dr. Gordon claims time is his greatest foe – and
who can argue given the extent of his commitments? In addition to his extensive clinical
and laboratory work, journal peer-review and
a position on a National Cancer Institute (NCI)
study section, Dr. Gordon also has responsibilities as the Chief of the Division of Hematology/
Oncology – responsibilities that include managing all faculty matters such as appointments,
promotions and salaries, overseeing Northwestern
Memorial Hospital’s hematology/oncology
inpatient unit, and heading up the hematology/
oncology practice in the faculty medical
practice group, Northwestern Medical Faculty
Foundation. He is as committed to teaching
as he is to research: he is responsible for the
three-year fellowship training program, which
currently has 20 fellows in various levels of
training, lectures to sophomore medical school
students and trains the hematology/oncology
residents. He has more than doubled the size
of the hematology/oncology division in the
past six years and has built up the program so
that it comfortably rests in the top 10 of cancer
programs in the country. Dr. Gordon believes
that people in leadership positions should strive
to create an environment where talented people
can succeed.
Dr. Gordon has clear designs on the future of
cancer. “Successful treatment of cancer lies in
the study of molecular biology and physiology
and the abilily and foresight to translate
that knowledge so that it can be applied to
patients. It’s figuring out what makes cells work
and what makes them get out of control, and
how to reverse that process.” With a wealth of
knowledge, skills and acumen, Dr. Gordon is
well on his way to achieving his goal.
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Leonidas C. Platanias, MD, PhD
A
native of Greece, Leonidas C. Platanias,
MD, PhD, initially became interested in
medicine as a child, perhaps the first glimpse of
his inventive spirit since no one in his family had
a medical background. He was first introduced
to oncology early in his studies at the University
of Patras Medical School in Patras, Greece,
where he earned his MD and PhD. “I learned
that so many were affected by cancer, and the
idea of helping such a significant number of
people made me realize the far-reaching implications of work in this field,” says Dr. Platanias,
and with this realization began his focused
medical aspirations.
At the University of Patras Medical School – a
new academic prototype based on the American
medical school model – the faculty were medical
professionals recently returned from teaching
and working in the United States. Dr. Platanias’
professors inspired and encouraged him to
continue his career in the U.S. upon graduation,
and in 1984 he landed a Fogarty Fellow position at the prestigious National Institute of
Health in Bethesda, Maryland. Researching
aplastic anemia, he began the immunology
studies that would subsequently play a role
in his career direction.
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After completing his research training at the
National Institute of Health, Dr. Platanias
began his internal medicine residency in 1986
at State University of New York in Brooklyn,
New York. Working in an extremely underprivileged urban area at the beginning of the AIDS
epidemic, he “saw a staggering number of AIDS
cases” which motivated him to also conduct
research on the hematology of the disease,
an unusual accomplishment for a resident.
Upon completing his residency and becoming
Board Certified in Internal Medicine – the first
doctor in his family – Dr. Platanias moved to
the Midwest in 1989 to become a fellow in
Hematology/Oncology at the University of
Chicago. It was during his fellowship that he
officially became a clinical oncologist and began
to research in the field that would become
his career specialty – molecular biology and
signal transduction.
Dr. Platanias’ first faculty appointment was
in 1992 as Assistant Professor of Medicine at
Loyola University in Maywood, Illinois, and
here he established his own lab and conducted
independent research. Securing a five-year grant
from the National Cancer Institute (NCI) to
study the role of IRS-proteins in Type IFN
signaling and a two-year grant from the
Department of Veterans Affairs to study signal
transduction of the interferon alfa receptor in
neoplastic calls, Dr. Platanias’ research notoriety
was on the rise. In 1993, he won the highly
recognized American Society of Clinical
Oncology, Young Investigator Award and was
honored with the prestigious American Cancer
Society Career Development Award from 1993
to 1996.
Joining the University of Illinois at Chicago
faculty as Associate Professor in 1996,
Dr. Platanias was promoted to Professor of
Medicine in 2001. He served as Chief of
Hematology/Oncology from 2000-2001
and was the Director of the Cellular Signaling
Program at the University of Illinois Cancer
Center from 2001-2002. It was at the
University of Illinois that Dr. Platanias’
expanded research endeavors achieved increased
national status and gained significant funding
support: a three-year grant (2001-2003) from
the American Cancer Society to study signaling
pathways mediating hematopoietic stem cell
suppression; a five-year grant (2002-2007) from
the National Cancer Institute to study signal
transduction of Type I interferons in malignant
cells; and a four-year grant (2002-2006) from
the National Cancer Institute to study the
mechanism of action of interferon in chronic
myelogenous leukemia.
In May of 2002, Dr. Platanias became the
Deputy Director of the Robert H. Lurie
Comprehensive Cancer Center of Northwestern
University. As an endowed Chair of the Lurie
family, Dr. Platanias is a Jesse, Sara, Andrew,
Abigail, Benjamin and Elizabeth Lurie
Professor of Oncology as well as a Professor of
Medicine at the Feinberg School of Medicine,
Northwestern University. About his decision to
come to Northwestern University, Dr. Platanias
shares, “Northwestern is a great university,
and the Robert H. Lurie Comprehensive
Cancer Center of Northwestern University has
become the premier facility of this type in the
region, a place of rapid growth and expansion
where I can realize both my academic and
professional aspirations.”
Dr. Platanias continues his grant-based molecular biology and biochemistry research in signal
transduction for cytokines in order to understand the mechanisms within the cancer cells
by which various substances affect functionality.
As Deputy Director, Dr. Platanias has many
oversight responsibilities in addition to his
research and teaching. He oversees the Shared
Resource Core Facilities, a network of 18 facilities that provide various support services for
investigators of the Cancer Center. He also
directs the development of the Cancer Center’s
efforts to procure new, significant research
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grants, especially funding from the National
Cancer Institute. Additionally, Dr. Platanias
chairs several search committees and supervises
the recruitment of new oncology faculty
and researchers for the Robert H. Lurie
Comprehensive Cancer Center of Northwestern
University.
Committed to involvement on a national scale,
Dr. Platanias currently participates on several
grant review committees: the National
Institute of Health CAMP Study Section; the
Department of Veterans Affairs Hematology
Merit Review Grants Subcommittee, where he
now serves as Chairman; and the Leukemia
Research Foundation Medical Advisory Board.
When asked about his professional goals,
Dr. Platanias emphasizes, “I want to contribute
to the Robert H. Lurie Comprehensive Cancer
Center of Northwestern University’s continued
expansion and success.” A key to that growth,
he believes, is the new Robert H. Lurie Medical
Research Center of Northwestern University, a
$200 million high-tech medical research facility
to be completed in early 2005 on the Chicago
campus. “The new Medical Research Center
will help us recruit high-caliber researchers,
build a stronger research structure and facilitate
the translation of clinical studies – taking
research from the bench to the bedside – which
is our ultimate goal.”
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Investigating the Possible Effects of
Tomatoes or Lycopene in Preventing
Prostate Cancer
Peter H. Gann, Susie Lee, Misop Han,
Ryan Deaton and Vijayalakshmi
Ananthanarayanan
Peter Gann, MD, ScD is an Associate Professor of Preventive
Medicine at Northwestern University’s Feinberg School
of Medicine, and a member of the Cancer Center’s
Cancer Epidemiology and Prevention Program.
Susie Lee, MPH is a Project Coordinator in the
Department of Preventive Medicine at Northwestern
University’s Feinberg School of Medicine.
Vijayalakshmi Ananthanarayanan, MD, is a Post Doctoral
Fellow in the Department of Preventive Medicine at
Northwestern University’s Feinberg School of Medicine.
Misop Han, MD, is an Assistant Professor in the
Department of Urology at Northwestern University’s
Feinberg School of Medicine.
Ryan Deaton is a Project Coordinator in the Department
of Preventive Medicine at Northwestern University’s
Feinberg School of Medicine.
B
y now, marketing from the food industry
has made many Americans aware of research
suggesting that lycopene – a compound found
in tomatoes – could have protective effects
against heart disease and cancer. Prostate cancer
is the disease most often implicated in this
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research, and as the most commonly diagnosed
cancer among men in the U.S., it amounts to
an expected 230,110 new cases and 29,900
deaths in 20041. Our group is engaged in
conducting a unique randomized clinical trial
at Northwestern that is aimed at clarifying the
direct effects of tomato on the prostate gland.
The first evidence suggesting a link between
tomatoes and prostate cancer risk arose from
epidemiological studies reported 8-12 years
ago. The most significant was based on the
Health Professionals Follow-up Study, a cohort
established at Harvard of over 44,000 male
health professionals who have regularly
recorded their dietary intake, other lifestyle
factors and specific health events since 19862.
The investigators computed the risk of developing prostate cancer in this cohort as a function
of the amount of dietary antioxidants, including
lycopene, consumed by the men. The results
were essentially negative for all antioxidants
(including β-carotene and vitamin E) except
lycopene. Risk of developing prostate cancer
was 21% lower among men in the highest
quintile for lycopene consumption compared
to those in the lowest quintile. Further analysis
showed that this risk reduction was primarily
attributable to men who ate more cooked
tomato products, such as tomato sauce. It had
been shown previously that cooking tomatoes
and eating them with oil substantially increases
the bioavailability of lycopene3.
The hypothesis was pursued by one of the
authors using blood samples available for
another Harvard-based cohort: the Physicians’
Health Study. Gann, et al analyzed plasma
samples collected and frozen in 1982 from 578
men in this cohort who subsequently developed
prostate cancer, and similar plasma samples from
1294 control men who were matched on age
and remained free of prostate cancer4. This study
design, referred to as a nested case-control study,
is a powerful way to estimate the association
between a biomarker and cancer risk using
10
archived samples collected long before, and
hence unaffected by, the disease of interest.
The results were strikingly similar to the findings
from the analysis of dietary intake – lycopene
was the only dietary antioxidant measured in
plasma that showed an inverse association with
prostate cancer risk. The results were stronger
for aggressive (advanced or high-grade) cancer
than for all cancers, suggesting a possible late
effect on progression. Figure 1 below shows the
relative risks for aggressive prostate cancer by
quintiles of plasma lycopene concentrations.
Figure 1. Relative risk (expressed as the odds ratio) of aggressive
prostate cancer by level of plasma lycopene, β-carotene and
placebo groups, The Physicians’ Health Study4.
Because the Physicians’ Health Study was a
randomized trial of β-carotene supplements, the
results were stratified to look at the β-carotene
and placebo groups separately. The group not
receiving β-carotene (placebo group) showed
a strong, linear inverse association between
lycopene level and risk (P for trend = 0.006).
Interestingly, there was no trend for lower risk
as lycopene increased in the β-carotene group;
however, compared to men in the group with
the lowest lycopene level and no antioxidant
supplement, the risk for prostate cancer was
significantly lower among all men taking
β-carotene. One interpretation is that an equivalent antioxidant benefit can be achieved either
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through eating a diet rich in lycopene or taking
β-carotene supplements.
Tomatoes are the predominant source of
lycopene in most diets, although significant
amounts can also be found in watermelon,
papaya, guava and pink grapefruit5. The chemical
structures of lycopene and β-carotene are shown
in Figure 2. Lycopene is a 40-carbon carotenoid
with 13 double bonds. β-carotene is formed
from lycopene by cyclization of its two end
groups. Because it lacks β-ionone rings, lycopene
cannot be cleaved to form vitamin A, which
means more remains available for antioxidant
activity. In addition, lycopene’s extra double
bonds and unusual stereochemical properties
contribute to its potent antioxidant effects. The
singlet oxygen quenching ability of lycopene
in vitro is at least twice as high as that of
β-carotene, and is higher than any other dietary
carotenoid studied6. These facts, combined with
the observation that, in most American populations, lycopene concentrations in serum are
higher than any other carotenoid, suggest that
the biological importance of lycopene was previously underestimated. Lycopene concentrations
in the prostate are particularly high, and are
correlated with serum levels7, 8.
Figure 2. The chemical structures of two related carotenoids:
Lycopene and β-carotene.
There is a danger in assuming that pure
lycopene supplements are the best type of agent
to study, however. Researchers learned from a
painful experience with β-carotene, that focusing on a single chemical in foods can sometimes
produce unexpected results. Despite decades of
research suggesting that men who ate diets rich
in β-carotene or had high blood levels experienced a reduced risk for lung cancer, two very
expensive Phase 3 randomized trials among
male smokers found that supplements actually
significantly increased the risk of lung cancer
(by about 20%) compared to placebo9. More
recently, an interesting animal study prompted
the same concerns about lycopene. Boileau
et al reported, in a well-controlled study using
the N-methyl-N-nitrosourea (NMU)-androgen
rat carcinogenesis model, that whole tomato
powder inhibited the development of prostate
cancer compared to a control diet, while a pure
synthetic lycopene supplement did not10. In the
tomato powder group, risk of developing lethal
prostate cancer was reduced by 26% compared
to controls, versus a non-significant reduction
of 9% in the group receiving pure lycopene. In
addition to lycopene, other known carotenoids
in tomatoes and tomato-based products include
β-carotene, γ-carotene, ζ-carotene, phytofluene,
and phytoene, all of which are among the 10
major carotenoids that are found to accumulate
in human prostate tissue11. There are also
numerous non-carotenoid compounds in tomatoes that have potentially relevant activity and
a large number of unknown phytochemicals as
well. Carotenoids generally occur in the plant for
a purpose, for example, to protect seeds in fruit
from photodegradation and oxidative damage.
From an evolutionary perspective, it makes sense
that plants would develop sets of interacting
compounds to accomplish these functions rather
than rely on single compounds12.
With all this in mind, we have designed our
current trial to evaluate the effects of a tomato
extract, which can be delivered in a capsule
with a consistent concentration of lycopene.
To produce the capsule, specially-bred (nongenetically modified) tomatoes are grown at a
facility in Israel (LycoRed Natural Products
Industries Ltd.), and water is removed, leaving
the complete lipid fraction from the tomatoes,
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literally tomato oil. Placebos using a red dye in
a lipid vehicle will also be used. Eligible participants will be men with high-grade prostatic
intraepithelial neoplasia (HGPIN), a lesion
believed to be a precursor to prostate cancer.
These men, who will be enrolled from the
Urology Clinic at NMH, normally undergo
repeated blind biopsy of the prostate. We will
obtain prostate biopsy samples before and six
months after random assignment to either two
capsules per day of tomato extract or placebo.
The daily dose, in terms of lycopene, will be
30 mg, which is the approximate level consumed
in food by the top decile of U.S. men. The
recruitment goal, over 18 months, is a total
of 80 patients.
The primary endpoints are specific molecular,
histological and nuclear changes in the posttreatment compared to pre-treatment biopsy
tissue. We have carefully selected a panel
of immunohistochemical markers including
proteins that have demonstrated differential
expression in the earliest phases of prostate
carcinogenesis; in particular during progression
from normal to preneoplastic phases. These
markers reflect disturbances in proliferation
(Ki67, mcm2), differentiation (PSA, chromogranin A), growth factor regulation (EGF
receptor, IGF-1), apoptosis (bcl-2, caspase 3)
and angiogenesis (CD34 for microvessel
density). In addition to standard IHC technique, an important aspect of this project will
be the application of computer-based image
analysis to provide more accurate, higher
throughput quantification of protein expression
in prostatic tissue. We will also investigate
differential expression of some of the chosen
markers in basal versus luminal epithelial cells,
because it appears that these cells behave differently during early prostate carcinogenesis.
AMACR – α-methylacyl-coenzyme A racemase –
has been shown to be strongly upregulated in
prostate cancer; expression in HGPIN is variable. We have found some staining for AMACR
in normal biopsy tissue, as demonstrated in
12
Figure 3, which shows a section containing
both normal glands and cancer. Highly variable
staining within the normal areas can be seen
within this single section. Recently, we have
found that patients who subsequently go on to
be diagnosed with prostate cancer have more
AMACR staining in their earlier normal biopsies
than patients who remain free of prostate
cancer. These results will be presented at the
Annual Meeting of the American Association
for Cancer Research in April, 2004.
Figure 3. Prostate section immunostained for AMACR. The
field displays normal glands with a wide range of AMACR
expression, including none (N1), light (N2), and heavy (N3),
as well as an area of cancer (Ca) showing heavy staining.
[magnified at 100x].
We are also working to develop a nuclear
morphometry index for the prostate that
combines information on nuclear size, shape,
DNA content and chromatin texture. To
accomplish this, we have collaborated with
Bacus Laboratories (Lombard, IL), which has
developed a computer-based image analysis
system for objective quantification of nuclear
grade in other chemoprevention settings13.
Briefly, this system takes a digital scan of the
tissue under the microscope and using special
software extracts nuclei from the image and
places them into orderly galleries. Once in
galleries, these nuclei are subjected to a large
array of measurements involving size, shape,
DNA content or texture parameters. Figure 4A
shows an example of such a gallery displaying
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normal prostate epithelial nuclei with perimeter
measurements from a single patient we have
studied. Figure 4B shows a graph of the distribution of nuclear grade scores (reflecting the
sum of several individual morphometric features)
from a patient with high-grade cancer compared
to a population of normal nuclei. The mean
nuclear grade score is 13.2 standard deviations
above the mean for normal nuclei. One can see
from the lack of overlap in the curves that this
approach provides a powerful way to detect
subtle changes in nuclear structure such as
those accompanying early neoplastic change.
investigational tools we are developing, will give
us a sound basis for designing the long-term
Phase 3 trials that will be needed to arrive at
definitive answers.
Acknowledgements
We wish to acknowledge the important contributions of several other individuals to this work,
including Irene Helenowski, MS, Erin Anderson,
Ximing Yang, MD, PhD, Robert Meyer,
Michael Pins, MD, James W. Bacus, PhD,
and Val Kagan, PhD.
Funding
Effort on this project is supported by R01 CA
90759-01A1 and P50 CA90386-02 grants
from the National Institute of Health and
the National Cancer Institute.
Figure 4. Figure 4A shows a gallery of normal prostatic nuclei
digitally-extracted from a Feulgen-stained slide with perimeter
measurements displayed. Figure 4B shows the distribution of
multi-feature nuclear grade scores for a high-grade prostate
cancer from the same patient compared to nuclear grade scores
from a pool of normal nuclei. Note that the mean nuclear
grade score in the cancer is 13.2 times above the mean for
normal nuclei.
In conclusion, it is too early to tell whether
tomatoes or lycopene have something to tell us
about how to prevent prostate cancer. It is our
hope, however, that trials like ours, and the new
REFERENCES
1. American Cancer Society. Cancer Facts and Figures 2004:
Estimated new cancer cases and deaths by sex for all sites,
US, 2004. http://www.cancer.org.
2. Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ,
Colditz GA,Willett WC. Intake of carotenoids and retinol
in relation to risk of prostate cancer. J Natl Cancer Inst.
1995;87(23):1767-76.
3. Stahl W,Sies H. Uptake of lycopene and its geometrical
isomers is greater from heat-processed than from
unprocessed tomato juice in humans. J Nutr.
1992;122(11):2161-6.
4. Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM,
Hennekens CH,Stampfer MJ. Lower prostate cancer risk
in men with elevated plasma lycopene levels: results of a
prospective analysis. Cancer Res. 1999;59(6):1225-30.
5. Clinton SK. Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev. 1998;56
(2 Pt 1):35-51.
6. Di Mascio P, Kaiser S,Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch
Biochem Biophys. 1989;274:532-8.
7. Clinton SK, Emenhiser C, Schwartz SJ, Bostwick DG,
Williams AW, Moore BJ,Erdman JW. cis-trans Lycopene
isomers, carotenoids, and retinol in the human prostate.
Cancer Epidemiol Biomarkers Prev. 1996;5:823-33.
8. Freeman VL, Meydani M, Yong S, Pyle J, Wan Y,
Arvizu-Durazo R,Liao Y. Prostatic levels of tocopherols,
carotenoids, and retinol in relation to plasma levels and
self-reported usual dietary intake. Am J Epidemiol.
2000;151(2):109-18.
9. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers.
The Alpha-Tocopherol, Beta Carotene Cancer Prevention
Study Group. N Engl J Med. 1994;330(15):1029-35.
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10. Boileau TW, Liao Z, Kim S, Lemeshow S, Erdman JW,
Jr.,Clinton SK. Prostate carcinogenesis in N-methyl-Nnitrosourea (NMU)-testosterone-treated rats fed tomato
powder, lycopene, or energy-restricted diets. J Natl
Cancer Inst. 2003;95(21):1578-86.
11. Paetau I, Khachik F, Brown ED, Beecher GR, Kramer
TR, Chittams J,Clevidence BA. Chronic ingestion of
lycopene-rich tomato juice or lycopene supplements
significantly increases plasma concentrations of lycopene
and related tomato carotenoids in humans. Am J Clin
Nutr. 1998;68(6):1187-95.
12. Gann PH,Khachik F. Tomatoes or lycopene versus
prostate cancer: is evolution anti-reductionist? J Natl
Cancer Inst. 2003;95(21):1563-5.
13. Bacus JW, Boone CW, Bacus JV, Follen M, Kelloff GJ,
Kagan V,Lippman SM. Image morphometric nuclear
grading of intraepithelial neoplastic lesions with applications to cancer chemoprevention trials. Cancer Epidemiol
Biomarkers Prev. 1999;8(12):1087-94.
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Four-Dimensional Elastic LightScattering Fingerprinting for Early
Detection of Colon Carcinogenesis
Hemant K. Roy, Ramesh K. Wali, Yang Liu,
Young L. Kim, Michael J. Goldberg and
Vadim Backman
Vadim Backman, PhD, is an Assistant Professor of Biomedical
Engineering at Northwestern University’s McCormick School
of Engineering and a Staff Member at the Department of
Medicine, Evanston Northwestern Healthcare. Dr. Backman
is a member of the Cancer Center’s Gynecologic Oncology
and Cancer Genes and Molecular Regulation Programs.
Hemant K. Roy, MD, is an Associate Professor in the
Department of Medicine at Evanston Northwestern
Healthcare/Northwestern University, and a member
of the Cancer Center’s Cancer Cell Biology and
Gastrointestinal Oncology Programs.
Michael J. Goldberg, MD, is the head of the Division
of Gastroenterology, Evanston Northwestern Healthcare.
He is also an Associate Professor at the Feinberg School
of Medicine, Northwestern University.
Ramesh K. Wali, PhD, is a Research Associate Professor
in the Department of Medicine at Evanston Northwestern
Healthcare/Northwestern University, and a member
of the Cancer Center’s Cancer Cell Biology and
Gastrointestinal Oncology Programs.
Young L. Kim is currently pursuing his PhD in biomedical
engineering from Northwestern University. His research
interests include early cancer diagnosis and
chemoprevention using light scattering.
Yang Liu is currently pursuing her PhD in biomedical
engineering at Northwestern University. Her research focus
has been working on the development of light-scattering
for the early cancer diagnosis.
C
olorectal neoplasms are the second leading
cause of cancer deaths in the United States,
underscoring the public health imperative for
developing novel strategies to combat this
malignancy1. Screening has been shown to
decrease colorectal cancer (CRC) mortality by
both identifying lesions at an early, potentially
curable stage and also through prevention of
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CRC development by targeting the precursor
lesions, the adenomatous polyps2. However,
there are many barriers to widespread implementation of these strategies including patient
non-compliance, discomfort, economic
constraints, resource availability, and complication risk3. Indeed, most eligible subjects do not
receive any type of CRC screening. Therefore,
it is clear that improved screening methodologies are essential to decrease the number of
CRC fatalities. Many screening techniques are
designed to exploit the “field effect” of colon
carcinogenesis, the proposition that the
genetic/environmental milieu that results in
neoplasia in one region should be detectable
throughout the mucosa4. While several histologic (e.g. rectal aberrant crypt foci (ACF),
cellular (e.g. apoptosis in the uninvolved
mucosa), molecular (e.g. colonic protein kinase
C activity) markers have shown a statistically
significant correlation between rectal assays and
colonic neoplasia, their performance characteristics are suboptimal for clinical practice. Novel
techniques to detect the field effect are, therefore, urgently needed.
There are several lines of evidence that subtle
perturbations in colonic micro-architecture
may be a manifestation of the “field effect”5-7.
While micro-architectural alterations may serve
as an excellent marker of the “field effect” of
colon carcinogenesis, current technology does
not allow its practical and accurate detection.
Advances in biomedical optics have the potential of enabling real-time in vivo assessment of
intracellular structure. Light scattering signals
are extremely rich and complicated, thus having
the potential of yielding unprecedented insights
into the micro-architectural organization of the
cell. Light scattering signals from intracellular
structures depend not only on size, shape, and
internal organization, but also on its position
as part of a cell itself or a larger organelle (the
immediate surrounding milieu of solid particles
such as proteins).
16
In order to realize the full promise of light scattering, we developed four-dimensional elastic
light-scattering fingerprinting (4D-ELF), a
new generation of optical technology8,9. This
technology allows us to obtain quantitative
information about biological structures without
the need for tissue biopsy, fixation, staining,
or other processing. 4D-ELF enables probing
tissue organization at scales from tens of
nanometers to microns, thus encompassing a
spectrum of structures ranging from macromolecular complexes to whole cells. Indeed, this
provides information about objects 20-50 times
smaller than can be detected by conventional
microscopy. Thus, the light scattering fingerprints provide a heretofore unattainable insight
into the architecture of living tissue at the
nanoscale organizational level. The data
obtained from light scattering fingerprinting
should not be considered as a mere substitution
for the morphological tissue analysis using light
microscopy. The four-dimensional information
extracted from ELF provides much greater
biological insights than the previously utilized
technologies. The critical advantages are related
to the quantitative information regarding nanoscale architecture on living tissues. 4D-ELF
gives information at the level of electron
microscopy and yet keeps the levels of cellular
organization that may be lost with staining/
fixation allowing hereto undiscovered insights
regarding micro-architectural changes that
occurs early in neoplastic transformation.
Our objective of this study was to assess
whether 4D-ELF would be able to detect the
field effect of colon carcinogenesis. In the
present studies, we tested 4D-ELF in the
azoxymethane (AOM)-treated rat, a well-validated model of colorectal carcinogenesis that
recapitulates many of the important morphological, genetic and cellular alterations seen in
human colon cancer10. We demonstrate that
4D-ELF is able to accurately identify alterations
in the colonic mucosa at a far earlier stage than
any previously described markers. Furthermore,
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these changes correlated well with the carcinogenic progression in this model.
Methods
Light Scattering Fingerprinting. We developed a specialized light scattering instrument
to measure comprehensive light scattering data
from living tissues. Briefly, a series of points
on a sample surface were illuminated by a
collimated linearly polarized light from a
Xe-lamp. A Fourier lens positioned in the
collection arm of the instrument projected the
angular distribution of the backscattered light
onto the slit of a spectrometer, which further
diverted this light now in the direction perpendicular to the slit according to its spectral
composition. The resulting 2D image, wavelength λ (400-700 nm) vs. scattering angle θ
(0°-7°), was projected onto a CCD (Roper
Scientific) for a given azimuth of scattering ϕ,
which was varied by rotating a polarizer in the
delivery arm of the system. The instrument also
measures two independent polarization components p of the scattered light: one polarized
along, I||, and orthogonally, I⊥, to the incident
polarization. Such 4D data (λ,θ,ϕ,p) provide
comprehensive information about the light
scattering and can serve as extremely sensitive
“fingerprints” of the specimen micro-architecture. Furthermore, the differential polarization
signal ∆I(λ) = I||(λ) – I⊥ (λ) is particularly
sensitive to the superficial tissue (<50µm), e.g.
epithelium. This is critical for early detection of
pancreatic precancer as it is of epithelial origin.
Signals I||, I||+I⊥, and I⊥ contain information
about progressively deeper tissues.
In order to analyze the light scattering signatures, we assayed a variety of parameters that
span the spectrum of micro-architectural abnormalities. The spectral slope analysis evaluates
size distribution of particles ranging from
macromolecules to organelles. Fractal dimension, on the other hand, reflects alterations of
the tissue organization at much larger scales,
ranging from large organelle to groups of cells.
Principle component analysis (PCA) is a standard data procedure for assessing underlying
structure in a data set. In order to infer relationship to colon carcinogenesis, we correlated
the 4D-ELF signatures with the subsequent
occurrence of ACF. Specifically, neoplastic
signatures should progress over time and be
predominantly in the distal colon especially
early during carcinogenesis (mirroring our ACF
data). All data from AOM-related signatures
were compared with an age matched salinetreated rat.
Animals. All animal studies were performed in
accordance with the institutional animal care
and use committee of Evanston-Northwestern
Healthcare Forty-eight (48) male Fisher 344
rats (150-200 g) were randomized equally
to groups that received either two weekly i.p.
injections of AOM (15 mg/kg) (Sigma, St
Louis Mo) or saline. Rats were fed standard
chow and were sacrificed at various time points
after second injection (2,4,5,6,8,12 and 20
weeks). Colons were removed, flushed with
phosphate buffered saline and divided into
equal proximal and distal segments. 4D-ELF
analysis was performed on fresh tissue. ACF
quantitation was performed on a subset of
animals using methods previously described11.
Results
The AOM-treated rat model is one of the most
robust and widely used models of colon cancer.
As in human carcinogenesis, in this animal
model, neoplasia progresses through a well
defined sequence of events. In AOM-treated
rats, the earliest detectable markers of carcinogenesis, ACF, develop in 5-12 weeks after the
AOM injection; adenomas are observed in
20-30 weeks, and carcinomas develop after
more than 40 weeks. No histologic, molecular
or genetic markers have been shown to be able
to detect earlier stages (<4-12 weeks) of colon
carcinogenesis. Here we report that light scattering fingerprints change profoundly as early
as 2 weeks after AOM-injection.
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We recorded ELF data from AOM-treated and
control rats at 2, 4, 5, 6, 8, 12, and 20 weeks
after AOM or saline injection. In order to
correlate ELF with a well-validated biomarker
of colon carcinogenesis, we analyzed ACF
number on a subset of animals in this study.
ACF were detectable at week 4 and progressively increased in both number and complexity
over the course of the experiment (data not
shown). There was a marked distal predominance in ACF. While proximal ACF did occur,
these required longer to develop and were less
numerous than distal ACF. There were no ACF
detected in the saline-treated animals.
Figure 1 shows representative light scattering
fingerprints recorded from rat colons 2 weeks
post-AOM treatment or age-matched control
animals. As evident from Fig. 1(a) and (b),
in the proximal colon, where the carcinogenic
effect of AOM is minimal, AOM-treatment
induces only modest changes in ELF. For
comparison, in the distal colon, the alterations
of the fingerprints are dramatic (Figs. 1(d) and
(c)), paralleling the carcinogenic efficacy of
AOM in the distal colon. We note that the time
point, for which the alteration of light scattering
fingerprints was detected (i.e. 2 weeks after
AOM-treatment), preceded the formation of
ACF or any other currently known markers
of colon carcinogenesis.
As outlined in the Methods, we identified
several light scattering markers that can be
obtained from the ELF data and are highly
significant for the earliest precancerous changes
in the colons of AOM-treated rats. These alterations in light scattering fingerprints indicate
that the nano/micro-architecture of tissue
changes even in the earliest stages of colon
carcinogenesis. Importantly, the changes in light
scattering markers follow both the spatial and
temporal progression of colon carcinogenesis
(Table 1 and Fig. 2). Moreover, the performance characteristics of light scattering markers
Table 1
Light Scattering
Marker
P-value (2-20 weeks
post AOM-treatment)
Spectral slope
<10–14
PC 1
<10–42
Df
<10–9
Table 1. Significance of light scattering markers of early colon
carcinogenesis measured using ANOVA. Spectral slope was
measured as the absolute value of the linear coefficient of the
linear fit to ∆I( λ) and characterizes the size distribution of
microscale tissue structures. PC – the first principal component
obtained using the principal component analysis of ∆I( λ). PC1
accounted for >90% of the data variance. Df – fractal dimension of tissue microarchitectjre measured as the linear slope of
two-point mass density correlation function C(r) in the linear
regions of log-log scale. (C(r)=<ρ(r)ρ(r’+r)>, where ρ(r) is a
local mass density at point r with 1 µm<r<50 µm.)
Table 2
2 weeks post
12 weeks post
AOM-treatment AOM-treatment
Figure 1. Representative 4D-elastic light scattering fingerprints
from rats sacrificed at 2 weeks after the AOM or saline injection. The color represents intensity of backscattering light. The
horizontal axis is the wavelength of the backscattering light.
The vertical axis is the backscattering angle. (a): Saline-treated
rat, proximal colon, (b): AOM-treated rat, proximal colon,
(c): saline-treated rat, distal colon, and (d): AOM-treated rat,
distal colon. As demonstrated, even at this very early time point,
AOM-treatment had a dramatic effect on 4D-ELF signatures
in the distal colon. However, in the proximal colon the changes
attributable to AOM treatment were quite subtle.
18
Sensitivity
92%
100%
Specificity
100%
100%
Positive Predictive Value
94%
100%
Negative Predictive Value
100%
100%
Table 2. Performance characteristics of light scattering-based
diagnosis using the markers listed in Table 1. 2 weeks post AOMtreatment: neoplastic changes cannot be detected using histologic
or molecular means; 12 weeks post AOMS-treatment: the earliest
time point when neoplastic changes can be detected histologically,
although with low sensitivity and specificity.
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dramatically exceeded all other conventional
and experimental markers for all time points
(Table 2).
Figure 2. Analysis of 4D-ELF information. (a): Changes in
the spectral slope at 2, 4, 5, 6, 12 and 20 weeks after the AOM
treatment in the distal colons of control and AOM-treated rats
obtained by means of the analysis of the spectral dimension in
ELF. (b): Changes in the fractal dimension of the superficial
mucosa obtained by means of the analysis of the angular dimension in ELF. (c): Principal component analysis (PCA) of light
scattering fingerprints: score of Principal Component 1 (PC1).
The changes in all three ELF markers are significant even
for the pre-ACF time point (2 weeks post AOM treatment).
Moreover, in agreement with the ACF data, the change in the
ELF markers was even more dramatic at the later time points.
Discussion
Exploitation of the “field effect” in colon
carcinogenesis is a common theme in colon
cancer screening. As previously discussed,
present strategies lack sufficient sensitivity
and specificity for optimal population screening.
Thus, the finding of an accurate marker for the
field effect would be of major clinical importance. Application of the newly developed
4D-ELF technology has great promise for colon
cancer screening because of the remarkable
sensitivity to the earliest changes in carcinogenesis. Utilizing quantitative analysis of tissue
micro-architecture, we were able to detect the
earliest alterations in neoplastic transformation
(at 2 weeks after carcinogen treatment) which
may reflect the “field effect”. The relevance
of these 4D-ELF changes to carcinogenesis
is supported by both the temporal and spatial
correlation. Temporally, the marked alterations
detected at week 2 progressively increased in
magnitude over time consonant with the
neoplastic effects of AOM in this model.
Spatially, the early signature alterations were
predominantly in the distal colon, the region of
the colon most susceptible to ACF and tumor
development. Moreover, the changes noted
with 4D-ELF occurred at 2 weeks after AOMtreatment, a time-point far earlier than seen
with other conventional biomarkers. This timepoint was of particular importance in that the
nonspecific genetic and cellular changes associated with acute effects of carcinogen have
dissipated12. Therefore, alterations at this time
reflect the earliest changes related to the field
effect of carcinogenesis. The biological mechanisms of this phenomenon are currently under
investigation. We believe that our data provide
compelling evidence that the micro-architectural perturbations in the histologically normal
mucosa identified by 4D-ELF represent a
reliable marker of the “field effect” of colon
carcinogenesis. Moreover, it is important to
note that despite the extensive “data-mining”
performed on 4D-ELF signatures, this represents less than 5% of total information available.
Therefore, it is conceivable that our findings of
early changes in carcinogenesis may be eclipsed
by future ELF analyses.
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In summary, this report demonstrates that the
newly developed technology, 4D-ELF was able
to detect heretofore unrecognized subtle microarchitectural perturbations from the field effect
of colon carcinogenesis. This technology has
promise of allowing accurate risk-stratification
and identifying patients who would benefit
from colonoscopic screening. One can envision
the rapid “bench-to-bedside” transition of this
technology through the development of an
endoscopically compatible probe with real-time
signature determination. Moreover, 4D-ELF
can give unparalleled insights into biological
changes early in carcinogenesis. Further
studies are being conducted to translate this
technology into clinical practice and to determine the biological determinants of these
micro-architectural alterations.
This study was supported in part by research
grants from the National Institutes of Health
(1R21CA102750-01), National Science
Foundation (BES-0238903), General Motors
Cancer Research Foundation, and American
Cancer Society-Illinois Division.
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Zack DL, DiBaise JK, Quigley EMM, Roy HK.
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4. Braakhuis B, Tabor M, Kummer J, Leemans C,
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7. Montag AG, Bartels PH, Dytch HE, Lermapuertas E,
Michelassi F, Bibbo M. Karyometric Features in Nuclei
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8. Kim Y, Liu Y, Wali RK, Roy HK, Goldberg MJ, Kromine
AK, Chen K, Backman V. Simultaneous Measurement
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The Mechanism by which EBNA1
Supports the Replication and
Partitioning of Latent EBV Genomes
Ashok Aiyar and John M. Sears
Ashok Aiyar, PhD, is an Assistant Professor of MicrobiologyImmunology at Northwestern University’s Feinberg School
of Medicine. Dr. Aiyar is a member of the Cancer Center’s
Viral Oncogenesis Program.
John Sears is a 5th year graduate student in the Integrated
Graduate Program with an academic focus in tumor cell biology.
He joined the Ashok Aiyar’s laboratory in April, 2001 as part
of the Microbiology-Immunology Department and was
partially funded through a carcinogenesis training grant.
E
pstein-Barr virus (EBV) is a gammaherpesvirus that infects B-cells and epithelial
cells. Epidemiological studies indicate that a
latent EBV infection is associated with proliferative disorders of lymphoid and epithelial cells
including infectious mononucleosis1, endemic
Burkitt’s lymphoma2, and nasopharyngeal carcinoma3. EBV is latent is these proliferating cells,
so that very few viral genes are expressed, and
no infectious virus is released4,5. EBV’s genome
is present as a nuclear plasmid within latently
infected cells. This plasmid is replicated once
per cell-cycle in synchrony with cellular chromosomes6. Further, in approximately 97% of
mitotic events, newly replicated viral genomes
are partitioned equally into daughter nuclei7.
This efficiency equals the efficiency observed for
the partitioning of plasmids containing chromosomal centromeres in yeast, indicating that the
partitioning of EBV genomes is an equally efficient process8,9. Once per cell-cycle replication
of viral genomes, and their subsequent equal
partitioning require a single viral protein, the
Epstein-Barr nuclear antigen 1 (EBNA1)10.
EBNA1 binds a region of the viral genome
termed the origin of plasmid replication (oriP).
Consistent with this central role for EBNA1 in a
latent EBV infection, it is the only EBV protein
21
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that is expressed in all malignancies associated
with EBV. OriP has two clusters of binding sites
for EBNA1, termed the dyad symmetry element
(DS), and the family of repeats (FR)11. EBNA1
bound to DS recruits the cellular origin recognition complex (ORC), and the cell-cycle
dependent MCM complex to DS, to initiate
DNA synthesis from oriP 12,13. EBNA1 bound
to FR is required to maintain EBV’s genome in
proliferating cells, and to partition genomes into
daughter cells14. Consistent with this, deletion of
FR from EBV eliminates the ability of the virus
to immortalize cells and establish latency 15.
Domains of EBNA1
We study how EBNA1 bound to FR mediates
the maintenance and partitioning of viral
genomes in proliferating cells. For this, we
make use of small plasmids that contain oriP
introduced into human cell-lines that express
wild-type EBNA1, or derivatives thereof. These
small oriP-plasmids are more readily manipulated than the large viral genome, but retain the
properties of being replicated once per cell-cycle
and then partitioned equally 14,16,17. EBNA1 is
schematically represented in Figure 1. The
C-terminal one-third of the protein (a.a. 451641) dimerizes and then specifically associates
with EBNA1-binding sites within the DS and
FR regions of oriP. The central one-third of the
‘A’
EBNA1
GLY GLY ALA REPEATS
+++
33
89
aa 41 GRGRGRGRGRGGGRP 54 (EBNA1)
GRGRGRGRGRGRGRP
(MBD2a)
GRGRP
(HMGA1a)
protein (a.a. 90-327) contains a repeat of
glycine-glycine-alanine. Most of this region can
be deleted without affecting EBNA1’s functions
in replication, maintenance or partitioning in
the context of human cell-lines in vitro 10,18. The
gly-gly-ala repeats are flanked on either side by
positively regions that we refer to as “A” (a.a
33-89) and “B” (a.a 328-378). Previous work
had demonstrated that chimeras of either of
these regions fused to GFP associated with
metaphase chromosomes 19. Region B also associates with a nucleolar protein, termed EBP2,
and it has been hypothesized that this interaction mediates EBNA1’s ability to partition
EBV genomes20,21.
EBNA1 is an AT-hook protein
In addition to being positively charged, both
region A and region B share a second characteristic. They contain alternating glycine and
arginine residues, as indicated in Figure 1.
Such repeats are found in cellular proteins that
bind metaphase chromosomes through a DNA
binding motif termed the “AT-hook”. In an
AT-hook, the alternating glycine and arginine
residues form a flexible interface that can closely
approach the minor groove of DNA. Within
the minor groove, there is a specific interaction
between the guanadino group of arginine and
O6 atom of thymidine22. This renders an AThook specific for AT-rich
DNA. Because EBNA1 had
NLS
(379386)
sequences resembling cellu‘B’
lar AT-hooks, we tested the
oriP BINDING / DIMERIZATION
328
378
641
451
hypothesis that domains A
and B of EBNA1 interacted
aa 329 GRGRGGSGGRGRGGSGGRGRGGS 350 (EBNA1)
with cellular chromosomes
GRGRP
GRGRP
(HMGA1a)
GRGRP
by functioning as AT-hooks.
+++
Figure 1. A schematic diagram of the functional domains of EBNA1, which also compares
the sequences of the presumptive AT-hooks within domains A and B to the known AT-hooks
of HMGA1a (Genbank accession number NM_145899) and MBD2a (Genbank accession
number NP_003918). The oriP-binding and dimerization domain are localized at the
carboxy-terminus of EBNA, comprised of amino acids 451-641 and is termed the ‘DBD’.
Upstream of the DBD is a nuclear localization sequence (aa 379-386). The amino-terminus
of EBNA1 is comprised of two functional, positively-charged domains, termed ‘A’ (aa 33-89)
and ‘B’ (aa 328-378) separated by a stretch of gly-gly-ala repeats (aa 90-327) not known to
be functional in the latent replication of EBV. Domain A of EBNA1 possesses a long stretch of
GR repeats that is almost identical to the AT-hook sequence found within of hMBD2a. The B
domain of EBNA1 also contains a stretch of GR repeats that possesses strong similarity with a
repeat of the classic AT-hook sequence GRGRP found within the HMGA1a protein.
22
For this, we examined
whether baculovirusexpressed EBNA1 would
specifically associate with
AT-rich DNA through the
use of a nitrocellulose filterbinding assay. Our assays
indicated that the binding
Page 23
full-length EBNA1
100
100
poly (dA.dT)
poly (dA.dT)
poly(dG.dC)
10
poly(dG.dC)
10
Phage Lambda
Phage Lambda
oriP
1
1
0
250
500
750
1000 1250 1500
0
Competitor (ng)
250
500
750
1000 1250 1500
Competitor (ng)
% poly(dA.dT) bound
% poly(dA.dT) bound
100
HMGA1a
B.
7 days
2A-DBD
+ Hoecsht33342
DNA Standards (pg)
100
300 1000
21 days
3A -DBD
A.
B.
HMGA1a
2A -DBD
A.
necessary for EBNA1 to function, we
constructed three derivatives of EBNA1 that
lacked domain B. In the first two, we deleted
domain B, and replaced it with either one
additional copy of domain A or two additional
copies of domain A. These derivatives are called
2A-DBD and 3A-DBD. In the third derivative,
we deleted the entire amino-terminus of
EBNA1, and replaced it with the cellular AThook protein, HMGA1a. This derivative is
called HMGA1a-DBD. We tested whether
2A-DBD and 3A-DBD, that lacked the ability
EBNA1
of EBNA1, or the cellular AT-hook protein,
HMGA1a, to a labeled poly(dA.dT) probe was
readily competed by cold poly(dA.dT), but not
by other nucleic acids such as phage lambda
DNA, poly(dG.dC) or even oriP (Figure 2A).
Additional assays performed with purified
peptides corresponding to domains A and B
confirmed that the AT-hook activity resided
in each of these domains. To confirm that the
binding was in the minor groove, we tested
whether association of domains A and B with
the labeled poly(dA.dT) probe could be
3A -DBD
2:26 PM
EBNA1
5/14/04
2A -DBD
85898 NUMS Journal
Domain A
75
Domain B
50
A
B
25
0
0.01
C
0.1
1
10
100
1000
Distamycin A (µM)
Figure 2. EBNA1 supports specific affinity for AT-rich DNA
in vitro. Purified peptides domain A or domain B of EBNA1
and full-length EBNA1were analyzed for their ability to
bind AT-rich, labeled oligonucleotides compared to full-length
HMGA1a in filter binding assays. (A) The association
of baculovirus-expressed EBNA1 and HMGA1a with a
poly(dA.dT) probe is specific, and competed effectively by cold
poly(dA.dT). In contrast, non-specific competitors such as
poly(dG.dC) and a HindIII-digest of phage lambda DNA do
not compete for the binding of these proteins with poly(dA.dT).
(B) The AT-hook synthetic analog, distamycin A, specifically
competes with the ability of domain A, domain B, and
HMGA1a to bind poly(dA.dT) probe. All binding assays were
performed using protocols described by the groups of Hurwitz
and Kelly.
competed by the minor groove binding drug
distamycin A (Figure 2B), as it is known to
compete the binding of HMGA1a from such a
probe23. These studies indicated that distamycin
A competed domains A and B from binding the
labeled poly(dA.dT) probe, providing evidence
that domain A and domain B bind poly(dA.dT)
in the minor groove, just as HMGA1a does22.
AT-hooks are required for the licensed
replication of EBV
Although both domains A & B are AT-hooks,
EBNA1’s ability to stably replicate and partition
oriP-plasmids has been postulated to occur
through the interactions of domain B with
EBP2. To test whether this interaction was
Figure 3. Versions of EBNA1 that bind DNA directly and lack
EBP2 binding function like wtEBNA1. (A) 2A-DBD binds
metaphase chromosomes. Metaphase chromosomes were isolated
from 293 cells stably expressing 2A-DBD stalled with colcemid.
Indirect immunofluorescence was performed using the K67.3
rabbit polyclonal antibody against the DBD of EBNA1.
Individual layer images (Z-sections of 100 nm) were captured
at 100X and deconvolved. 2A-DBD, as well as 3A-DBD (not
shown) were observed to localize to metaphase chromosomes in
discrete punctate spots that resemble those observed with wild-type
EBNA1 or HMGA1a-DBD. (B) 2A-DBD and 3A-DBD
support the episomal replication of oriP-plasmids. 10 mg of
AGP74 replication reporter in 293/EBNA1 and 293 derivatives and propagated with puromycin selection for 7 or 21 days.
At these times, DNA was extracted, digested with DpnI and
linearized with XbaI and analyzed by Southern blot, using
probes made from plasmid pPUR-DS (AGP83). The cell line
used for each transfection is indicated above each set of lanes,
and the days post-transfection is indicated above each sets of
lanes. The amounts of standards loaded are indicated above each
lane, and their electrophoretic mobilities are indicated by “A”.
“B” indicates the electrophoretic mobility of the linearized episomal plasmids. 2A-DBD and 3A-DBD supported stable
replication of this plasmid at similar levels to wild-type EBNA1.
to associate with EBP2 could still bind
metaphase chromosomes. A representative
analysis with 2A-DBD is shown in Figure 3A,
where the EBNA1 derivative can be observed
as bright speckles on Hoechst-stained chromosomes. Thus an interaction with EBP2 is not
required for EBNA1 to bind chromosomes.
We also tested whether these proteins would
support the stable replication of oriP-plasmids.
23
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Page 24
This analysis is shown in Figure 3B. For this, an
oriP-plasmid was transfected into cells expressing wild-type EBNA1, 2A-DBD or 3A-DBD.
Plasmids were recovered either seven days or
twenty-one days post-transfection, and the
amount of replicated (DpnI-resistant) DNA was
quantified by Southern blot. As shown in the
Figure, both 2A-DBD and 3A-DBD permitted
the replication of an oriP-plasmid at levels
comparable to wild-type EBNA1.
These studies indicate that versions of EBNA1
that contain an AT-hook are sufficient to mediate licensed oriP replication. In previous studies
we have demonstrated that oriP-plasmids have
to be tethered to metaphase chromosomes for
them to be replicated in the ensuing S-phase24.
Others have shown that the oriP-binding
domain of EBNA1 is not sufficient by itself to
support the replication of oriP-plasmids25,26. One
model that reconciles these varied observations
relies on recent observations that like EBNA1,
the ORC complex also associates with AT-rich
DNA27,28. Thus we believe it likely that an interaction between EBNA1 and ORC is first
mediated by their common localization to
AT-rich DNA, on metaphase chromosomes,
permitting the subsequent replication of oriPplasmids in S-phase.
This model explains why the entire aminoterminus (a.a. 1-450) of EBNA1 can be
replaced by any protein that binds AT-rich
DNA (see below), and yet leave EBNA1
competent to support oriP-replication. On the
other hand, deletion of this region creates a
derivative of EBNA1 that lacks AT-hooks and
is incapable of supporting oriP-replication.
AT-hooks are required for the partitioning
of EBV genomes
What about the third derivative of EBNA1,
HMGA1a-DBD? Experiments performed
with multiple oriP-plasmids and this derivative
of EBNA1 indicated that it supported the
replication of oriP-plasmids at levels that were
quantitatively very similar to that supported by
24
wild-type EBNA124. This result suggested to
us that it was likely that HMGA1a and EBNA1
bound cellular chromosomes through similar
mechanisms, i.e. EBNA1 tethered to chromosomes through AT-hooks just as HMGA1a did.
Plasmids are missegregated and lost when there
is a failure in the tethering mechanism. If both
these proteins functioned similarly, we would
expect that just as EBNA1 partitions plasmids
equally in approximately 97% of all mitoses, so
should HMGA1a-DBD. To test this, we transfected an oriP-plasmid into cells expressing either
EBNA1 or HMGA1a-DBD, and followed the
loss of this plasmid as a function of the number
of cell divisions. This analysis is shown in Table
1. The calculated rate of loss for EBNA1 was
3.6% per cell-generation, and HMGA1a-DBD
was 3.5% per cell-generation. Therefore we
believe it is likely both proteins bind chromosomes through similar mechanisms.
Cell line
8
Avg copy no.a (% of total)
on day posttransfection:
12
16
21
293/EBNA1
100 85.4 ± 7.6 74.8 ± 11 60.9 ± 14
293/HMGA1a- 100
90 ± 23 .985 ± 21 .71.8 ± 7.2
DBD
% Plasmid
loss per cell
generation
3.6
3.5
a Average copy number of DpnI-resistant, replicated plasmids maintained
in the absence of selection, represented as a percentage the number of
plasmid copies after 8 days.
Table 1. Rate of loss of replicated oriP-BamHI-C-luciferase
over time in the absence of selection in 293/EBNA1 and
293/HMGA1a-DBD cells
A model for how EBNA1 might partition
EBV genomes
Studies from a number of groups have shown
that eukaryotic chromosomes are not uniformly
condensed. They contain highly condensed Qbands interspersed with less condensed R-bands
that are AT-rich. These AT-rich R-bands have
been termed as scaffold attached regions
(SARs)29-35. HMGA1a, and other AT-hook
proteins have been localized to these regions32,3638
, and when visualized on metaphase
chromosomes appear as a series of punctate dots
on a chromosome (Figure 4A). While we have
no direct evidence that EBNA1 associates with
SARs on metaphase chromosomes as HMGA1a
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Page 25
does, the distribution of EBNA1 and
HMGA1a-DBD on metaphase chromosomes
cannot be distinguished, and the maintenance
of oriP-plasmids by these two proteins is mathematically identical. If EBNA1 were to localize
to a SAR on an interphase chromosome, it is
possible that after S-phase, EBNA1 along with
the replicated daughter oriP-plasmid is distributed to the sister SAR on the sister chromatid.
The indirect immunofluorescence analysis of
some of our metaphase spreads indicates that
the distribution of EBNA1 “dots” on some
sister chromatids is approximately equal, an
observation that is also true for HMGA1a-DBD
(See Figure 4A). In this model that is presented
schematically in Figure 4B, the per-replicon
partitioning event is simply the distribution
of EBNA1 to the sister SAR on the newlyreplicated sister chromatid. Replication of
A.
293/HMGA1a-DBD
293/EBNA1
Figure 4
B.
oriP
plasmid
Q band
S PHASE:
Replication of cellular chromatin
and oriP plasmids;
R band
(SARs)
Partitioning of oriP plasmids onto
sister SARs on sister chromatids
EBNA1
Transcription modulation of
cellular genes via AT-hooks
(and aa 65-89)
Figure 4: A proposed model for the partitioning of oriP-plasmids
on a per-replicon basis. (A) High resolution indirect immunofluorescence comparing the localization of wild-type EBNA1
and HMGA1a-DBD on metaphase chromosomes using an
antibody against the DBD of EBNA1. The localization of both
proteins were similar; many pairs of sister chromatids contained
an equal number of dots for both proteins. In several instances,
the dots were symmetrically positioned on both sister chromatids.
(B) A model of a portion of a chromosome based on the models
constructed by Laemmli and co-workers. For convenience we
have depicted a metaphase chromosome with Q-bands and
R-bands containing AT-rich SARs. Laemmli and co-workers
have demonstrated that sequences present as SARs on interphase
chromosomes are present in R-bands in metaphase chromosomes.
EBNA1 or HMGA1a-DBD tethers oriP-plasmids to SARs that
are present relatively infrequently compared to other sequences on
chromosomes. Upon S-phase, when there is replication of
chromosomes, we propose that there is a partitioning event of the
replicated oriP plasmids to the sister SARs on sister chromatids,
by a distribution of EBNA1 or HMGA1a-DBD to each sister
SAR. Key to this model is that the actual partitioning event
is concomitant with replication, and occurs during S-phase.
The plasmid remain tethered to sister chromatids and piggy-back
on the sisters during mitosis.
chromosomal DNA may be sufficient to very
transiently displace EBNA1 bound to a SAR
and permit reassociation with SARs on both
sister chromatids.
AT-hooks are not sufficient for EBNA1
to activate transcription
In addition to mediating the replication
and partitioning of EBV genomes, EBNA1
activates transcription from at least three
EBV promoters39-41. The mechanism by which
EBNA1 activates transcription is not clear. It
has been reported that EBNA1 activates transcription from episomal reporter plasmids by
facilitating their retention within transfected
nuclei42. If this were the only mechanism by
which EBNA1 activates transcription, we would
expect that HMGA1a-DBD and wild-type
EBNA1 would activate transcription to equivalent degrees as both proteins support plasmid
maintenance to similar levels. However, another
region of EBNA1 (a.a. 65-89) has been mapped
recently outside of the AT-hook regions as
a possible transcription activation domain43.
To determine whether the sole mechanism
by which EBNA1 activated transcription was
via plasmid retention, we tested the ability of
EBNA1, HMGA1a-DBD, or just the DBD
to activate transcription from an integrated
EBNA1-dependent transcription reporter in
BJAB cells. Our results indicate that EBNA1
can transcription from this reporter, while
HMGA1a-DBD does not activate transcription
to any level above the DBD alone (Figure 5).
Thus while the AT-hooks of HMGA1a can
substitute for the amino-terminus of EBNA1 to
support the replication and partitioning of EBV
plasmids, they are insufficient to support transcription activation to the same level as EBNA1.
Cellular AT-hook proteins function in number
of processes including replication, chromatin
remodeling, recombination, and enhanceosome
formation. Some of them are oncogenic. Our
future studies will investigate whether EBNA1’s
AT-hooks allow it to substitute for a cellular
AT-hook protein in any of these processes.
25
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Page 26
16
Relative Luciferase Activity
14
12
10
8
6
4
2
0
H
M
G
A
3.
1
-D
1a
1
A
A
N
N
D
EB
BD
D
pc
BD
Figure 5. Transactivation of an integrated FR-HSV1-TKluciferase reporter in BJAB cells by EBNA1 and HMGA1a-DBD.
BJAB cells containing an integrated FR-HSV1-TK-luciferase
reporter were electroporated with the control plasmid
pcDNA3.1, or expression plasmids for the EBNA1 DBD (DBD),
wild-type EBNA1 (EBNA1), or HMGA1a-DBD. along with
an EGFP expression plasmid. Two days after
transfection cells were FACS profiled for EGFP expression to
normalize for transfection efficiency, following which cytoplasmic extracts were prepared and examined for luciferase activity.
The bars indicate the relative luciferase activity observed over
electroporation of the control plasmid pcDNA3.1. The results
indicate that while EBNA1 can clearly transactivate an
integrated transcription reporter with EBNA1 binding sites,
HMGA1a-DBD does not transactivate this reporter over and
above any effect of the DBD alone.
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27
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Filopodia Formation and
Cancer Metastasis
Gary Borisy and Danijela Vignjevic
Danijela Vignjevic was a graduate student in the Integrated
Graduate Program and was supported by the Cancer Center’s
DOD Breast Cancer Training Grant. She recently began a
postdoctoral position at the Institut Curie in Paris, France
where she is continuing her studies of metastasis.
Gary Borisy, PhD, is the Leslie B. Arey Professor of Cell
and Molecular Biology at Northwestern University’s
Feinberg School of Medicine and Associate Vice President for
Biomedical Research. Dr. Borisy is a member of the Cancer
Center’s Tumor Invasion, Metastasis and Angiogenesis Program.
28
M
ost anticancer therapeutic drugs target
aspects of cell proliferation and have
deleterious side effects on rapidly renewing cell
populations such as those of the hematopoietic
lineage or intestinal lining. In comparison to
antiproliferatives, little success has yet been
attained in developing therapeutics effective
against metastasis. Yet, secondary metastases
in vital organs are often the cause of mortality.
Metastatic cancer cells have the capacity to
escape from a primary tumor, invade the
surrounding tissue, cross the endothelial wall of
capillaries, become carried through the circulatory system to distant locations, re-cross the
endothelial wall and establish secondary tumors
in previously unaffected tissues. Identifying the
triggers for metastasis and understanding the
individual steps of the process have been difficult due to its complex and multifaceted nature.
One hallmark of many cancer cells that is
thought to be critical for their acquisition of an
invasive phenotype is the abundant expression
of exploratory, sensory organelles known as
filopodia. An understanding of the mechanism
of filopodia formation holds the promise of
identifying molecular targets for the development of novel anti-cancer therapeutic drugs.
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Filopodial function
Filopodia are thin, spike-like protrusions of the
cell surface that have at their structural core a
bundle of 15-20 actin filaments cross-linked into
a stiff array. The tip of a filopodium contains a
complex of molecules specialized for signaling
and adhesion as well as for organizing the
bundle of actin filaments. The actin filaments
themselves are all oriented in parallel with their
so-called barbed (fast growing) ends toward the
filopodial tip1. The main cross-linker of the actin
filaments is a protein known as fascin.
Most cell types use filopodia as sensing organs
to explore the extracellular matrix (ECM) and
surface of other cells. In the growth cones of
migrating axons, filopodia sample the local environment and efficiently scan a wide terrain as
sensory antennae, searching for guidance cues
that allow the growing axon to navigate over
long distances and find its appropriate target2.
Filopodia have a role in cell adhesion and cell
spreading3. Many morphogenetic events in
embryonic development require two free
epithelial edges to fuse together and create a
continuous epithelium. This fusion process is
accomplished by filopodia extending from adjacent epithelial cells and interdigitating with each
other4. Filopodia also appear to serve as locomotory organelles; e.g. in fibroblasts grown in
a three-dimensional matrix of collagen fibers
and cells that wander through fluid filled spaces
in the body, such as neutrophils5. Cancer cells
become metastatic by acquiring a motile and
invasive phenotype. Recent evidence suggests
that this step requires the remodeling of
the actin cytoskeleton and the expression
of abundant filopodia6.
How are filopodia built?
We studied the mechanism of filopodia formation in two model systems: in vitro using
cytoplasmic extracts7, and in vivo using B16F1
melanoma cells8 (Fig. 1). In the vitro system,
filopodial-like bundles of actin filaments are
induced to form on plastic beads. The beads
are coated with activators of the Arp2/3
Figure 1. Filopodial filaments originate from the surrounding dendritic network. Platinum replica EM. (A) Structural
organization of stars. Actin filaments form a dendritic network
around the bead and filament bundles away from the bead.
Bar, 0.5 µm. (B) Filopodium contains a tight bundle of actin
filaments, which splays at its root and becomes an integral part
of the surrounding network. Bar, 0.2 µm.
complex which initially nucleates the formation
of a branched or dendritic network of actin filaments. Under suitable conditions in vitro, the
ultimate result is what we have called “stars”:
actin bundles radiating from the bead. Actin
filaments in these bundles, like those in filopodia, are long, unbranched, aligned, uniformly
polar, grow at the barbed end and have a
dendritic network at their roots. Our kinetic
and structural investigation of filopodial initiation demonstrated that these filopodial bundles
were formed by gradual reorganization of the
dendritic network in a process that we have
termed the convergent elongation mechanism
and that involves elongation of a subset of
dendritic filaments, self-segregation of these
filaments into filopodial precursors, and initiation of bundling at the tips of the precursors
(Fig. 2). This mechanism recognizes three
necessary processes for filopodia formation:
nucleation, elongation and bundling.
Nucleation
The Arp2/3 complex is thought to play a
role in filopodia formation because one of its
activators, N-WASP, induces filopodia in cells9.
However, since Arp2/3 is absent from established filopodia8,10, one may infer that it likely
participates in initiation, not in steady state
elongation of filopodia. In our in vitro system,
formation of filopodia-like bundles indeed
depended on the presence and activity of the
Arp2/3 complex7. Our data suggested that
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actin filament nucleation mediated by Arp2/3
complex could provide a source of filaments to
be rearranged into a bundle by gradual fusion.
Figure 2. Convergent elongation model for filopodia formation.
Based on our findings we propose a convergent elongation model
for filopodial initiation, which stipulates that filopodia are
formed by reorganization of the dendritic network formed in an
Arp2/3-dependent manner. The key assumption of this model is
that some filaments within the lamellipodial dendritic network
acquire privileged status by binding a set of molecules to their
barbed ends, which protect them from capping and mediate association of barbed ends with each other upon collision. Ena/VASP
proteins are likely candidates for the role of protection from
capping. Multiple collisions of privileged filaments during
elongation lead to gradual clustering of their barbed ends and
multimerization of associated barbed end complexes. The filopodial tip complex initiates filament cross-linking by recruiting
and activating fascin, which allows the bundling process to keep
pace with elongation and guarantee efficient pushing.
Elongation
Filopodia elongate by addition of subunits at
their tip. Normally, in cells, elongation of actin
filaments is terminated by capping protein11.
Thus, for filopodia to elongate continuously,
actin filaments need to be protected from
capping. A mechanism for protection is likely to
involve proteins of the Ena/VASP family based
on several findings: these proteins are enriched
at filopodial tips12,13, they antagonize the terminating activity of capping protein in vitro,
and their depletion from or targeting to the
membrane leads to shorter or longer filaments,
respectively14. It is attractive to speculate that
the presence of Ena/VASP at filopodial tips
in the cell prevents filament termination and
allows filopodial elongation.
In vitro, filopodial-like bundles were reconstituted in a pure protein system in which filament
nucleation, elongation and bundling were
allowed, but barbed end capping proteins were
lacking7, thus avoiding termination and obviating the need for protection against termination.
This result has been confirmed in vivo.
Specifically, recent data from our laboratory
30
(Mejillano et al., unpublished data) showed
that filopodial formation could be induced in
melanoma cells by depletion of capping protein
(CP) using an siRNA approach. The overall
conclusion is that depletion of CP favors
filopodia formation.
Protection of actin filaments from capping by
association of Ena/VASP at the actin filament
barbed constitutes a “privileged” status.
However, the persistent elongation of actin filaments by itself would not result in their local
accumulation unless they were able to associate
with each other. Consistent with this idea, we
found a structural interaction between filament
barbed ends which was mediated by a filopodial
tip complex8. The molecular composition of the
filopodial tip complex remains to be established.
Nevertheless, we may conclude that the
combination of continuous elongation and
self-association properties of privileged barbed
ends allows one to explain how the privileged
filaments in the dendritic network become gradually self-segregated during filopodial initiation.
Bundling
Actin filaments are not individually very stiff.
Consequently, to enable filopodia to efficiently
push, they must be cross-linked into a bundle
during the course of actin polymerization.
Fascin is one good candidate for the major
bundling protein of filopodia, but a number of
other proteins are also able to cross-link actin
filaments and are thought to be responsible for
formation of parallel actin bundles in vivo15,16.
Consequently, we evaluated which of the
known actin cross-linkers were present in the
native filopodia of melanoma cells. Fascin was
enriched in filopodia whereas other possible
cross-linkers, α-actinin and espin were not.
Microarray expression analysis (A. Biyasheva,
unpublished data) revealed that espin, villin and
L-fimbrin were not expressed in B16F1 cells,
which is understandable since these proteins are
known to have limited tissue distribution. Thus,
none of the investigated actin-bundling proteins,
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besides fascin, localized significantly to filopodia. Although the contribution of an as yet
unidentified cross-linker cannot be excluded,
the results of the molecular marker analysis
are consistent with the conclusion that fascin
is the major bundling protein in filopodia of
melanoma cells.
Fascin – major bundler in filopodia
Fascin was discovered by Kane et al. in the
1970s as a 55 kDa protein17. It was named
fascin because of its ability to form tight and
stable unipolar bundles with F-actin (from
Latin, fasiculus, a bundle). Since fascin is a
monomeric globular protein18 it must have two
actin binding sites. One putative actin binding
site is identified with residues 29-42, a highly
conserved region in all fascins19. Another site
has been deduced to lie at the C-terminus of
the molecule20.
The first cloned human fascin (fascin 1) is
highly similar in vertebrates and invertebrates19.
It is expressed in many vertebrate tissues with
particularly high expression in brain. Fascin 1
is not uniformly expressed in all cell types. It
appears to be low or absent in epithelial cell
lines, but is expressed at high levels by neurons,
glial cells, dendritic cells and many epithelial
tumor cells19. Transformed cells express 5-12
times more fascin than the level observed in
normal cells21. Dramatic increases in fascin
expression have been noted in many cancers,
lymphocytic disorders and hyperplasias.
Correlation between fascin expression and
tumor stage has been reported in many cancers;
e.g. pancreatic ductal adenocarcinomas22, largecell neuroendocrine carcinomas and small-cell
lung carcinomas23, follicular dendritic cell
tumor24, skin neoplasia25, ovarian cancer26 and
breast cancers27. Specifically, loss of hormone
receptor status in breast carcinomas is associated
with increased tumor cell motility and invasiveness. In an immunohistological study of breast
cancers estrogen receptor level was inversely
correlated with the expression of fascin. Thus,
the up-regulation of fascin in hormone receptor-negative breast cancers may contribute to
their more aggressive behavior27. Further,
the over-expression of c-erbB-2/ HER-2, a
receptor tyrosine kinase, correlates with poor
prognosis in patients with breast and ovarian
cancer. It has been determined that overexpression of c-erbB-2 is associated with
dramatic increases in mRNA and protein levels
of fascin27,28. Finally, fascin expression is used
as a diagnostic marker for particular forms of
cancer27,28. Examples are: Reed-Sternberg cells
as a long-recognized hallmark of Hodgkin’s
lymphoma, interdigitating dendritic cell sarcomas and Epstein Bar virus-transformed B cells.
Although, fascin is localized in filopodia,
no functional test had been performed as to
whether it is required for their formation. We
used targeted depletion by RNA interference as
a direct way to investigate the role of fascin in
filopodia formation. We prepared a hairpin
siRNA expression vector with a GFP marker,
pG-Super29 which is based on the pSuper
vector30 and modified to express EGFP under a
separate promoter for the added advantage of
easier detection and sorting of expressing cells.
The selected sequences did not have significant
similarity to any other known genes in the
mouse database as determined by BLAST
search (NCBI). Thus, these hairpin siRNA
constructs were designed to silence fascin without affecting other targets. Two approaches
were used to control for the specificity of silencing: expression of siRNAs with mismatching
nucleotides and rescue of the knockdown
phenotype by expressing a fascin gene that
was refractory to silencing. Fascin silencing in
mouse B16F1 melanoma cells at the protein
level was assayed by immunoblotting and
immunostaining. The phenotype of fascindepleted cells was analyzed by light and electron
microscopy. Fluorescence microscopy after phalloidin staining (Fig. 3A) showed that 4 days of
expression of fascin siRNA caused significant
decrease in the number of filopodia in cells,
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dorsal surface. The total length
of filopodial bundles including
their internal and protruding
parts was also increased after
expression of the S39A mutant,
and this increase was entirely
due to their protruding parts.
In contrast, expression of the
S39E mutant, which mimics
the inactive state, resulted in an
approximately 2.5-fold reduction
in the number of filopodia. In
addition to opposite effects on
Figure 3. Effect of fascin depletion and fascin mutant expression on filopodia
number in mouse melanoma cells. (A) Distribution of actin revealed by phalloidin
filopodia formation, we found
staining. Asterisk labeled filopodia is enlarged below. (B) Number of filopodia per 20
striking differences in the distriµm of cell perimeter. (C) GFP-fascin distribution in filopodia. (D) Relative fluorescent intensity vs distance from the tip of filopodia. Grey is actin and black is fascin.
bution of two fascin mutants in
filopodial bundles (Fig. 3C).
whereas their lamellipodia looked unaffected.
Fluorescence intensity profiles of GFP-fascin
To quantify the extent of filopodia inhibition,
and phalloidin-stained actin in filopodia showed
we determined the number of filopodia per unit
that distributions of wild type fascin and active
length of the cell leading edge and found a 4-5
S39A mutant paralleled that of actin, although
fold decrease in filopodia in fascin-depleted
there were some differences in the detailed
compared to control cells (Fig. 3B). The few
shape of the profiles (Fig. 3D). Such distriburemaining filopodia were wavy and loosely
tion is consistent with an idea that these fascins
bundled as determined by electron microscopy.
are targeted to filopodia primarily through their
interaction with actin. In contrast, inactive
Specific recruitment of fascin to filopodia
S39E mutant was highly enriched at filopodial
suggests a regulatory mechanism for fascin
tips and its fluorescence intensity rapidly
targeting. Previous works have shown that
declined proximally away from the tip, which
PKCα-driven phosphorylation of fascin at serine
sharply contrasted the more flat distribution
39, inhibits fascin binding to F-actin in vitro20,31.
of actin. Therefore it is plausible to assume
To examine the relationship between the serine
a second mode of inactive fascin binding in
39 phosphorylation and the filopodia formafilopodia that is not directly dependent on actin.
tion, we introduced point mutations into the
In conclusion, by several complementary funcfascin sequence to mimic the dephosphorylated
tional approaches we demonstrated that fascin
(S39A) or phosphorylated states (S39E). We
is the major cross-linking protein in filopodia,
expressed these mutants as GFP-tagged proteins
which plays a critical role in their formation
in melanoma cells and analyzed the efficiency of
and protrusion by bundling filopodial actin
filopodia formation, structural organization of
filaments and providing them with stiffness
filopodia and kinetics of different fascin mutants
necessary for pushing.
in expressing cells. Expression of S39A or S39E
fascin mutants produced differing phenotypes in
The role of fascin in cell migration has been
terms of length and frequency of filopodia. The
investigated by direct perturbation of the actinS39A mutant, which mimics the active state,
fascin interaction using antibodies reactive with
induced overabundant filopodia extending
the actin-binding sites of fascin, which inhibit
laterally from cell edges as well as from the
binding of fascin to actin. Introduction of these
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antibodies into cells completely prevented cell
spreading and migration on TSP-1 and also
partially blocked cell migration on fibronectin32.
However, in a different study, it was reported
that although fascin-overexpression correlated
with the formation of dynamic cell protrusions,
the presence of these finger-like protrusions
did not show a clear correlation with increased
locomotion for cell colonies on planar substrata33.
On the contrary, overexpression of fascin was
reported to significantly increase the migration
activity of epithelial cells in three-dimensional,
trans-filter assays21,33. Similarly, melanoma cells
transfected with fascin exhibited increased
migration compared with untransfected cells,
an effect that was augmented by addition of
NGF. Furthermore, the directed migration of
melanoma cells towards NGF was inhibited
by expression of mutated fascin S39D34. Thus,
fascin by participating in the formation of cell
protrusions may promote cell migration in vivo
in three-dimensional matrices. We propose that
fascin may promote metastasis of cancer cells
by participating in the formation of filopodia.
However, overexpression of other molecules
involved in filopodia formation could also facilitate metastasis. An example could be ezrin, a
cytoskeletal linker between the plasma membrane
and actin filaments which has been found to be
associated with metastasis of certain cancers35.
Conclusion
Cancer metastasis is a significant problem and a
tremendous challenge to drug discovery relative
to identifying key therapeutic targets as well
as developing breakthrough medicines. We
propose that key molecules involved in filopodia
formation such as fascin and its regulatory
elements could serve as potential novel targets
for the treatment of metastatic cancers.
The authors gratefully acknowledge support from
NIH grant GM62431 (GGB) and the DOD
Breast Cancer Training Grant (DV).
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10. Svitkina, T.M. & Borisy, G.G. Arp2/3 complex and actin
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12. Lanier, L.M. et al. Mena is required for neurulation and
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15. DeRosier, D.J. & Tilney, L.G. F-actin bundles are
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16. Bartles, J.R. Parallel actin bundles and their multiple
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17. Bryan, J. & Kane, R.E. Separation and interaction of the
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207-24 (1978).
18. Yamashiro-Matsumura, S. & Matsumura, F. Purification
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19. Kureishy, N., Sapountzi, V., Prag, S., Anilkumar, N. &
Adams, J.C. Fascins, and their roles in cell structure and
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20. Ono, S. et al. Identification of an actin binding region
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fascin. J Biol Chem 272, 2527-33 (1997).
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21. Yamashiro, S., Yamakita, Y., Ono, S. & Matsumura,
F. Fascin, an actin-bundling protein, induces membrane
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22. Iacobuzio-Donahue, C.A. et al. Highly expressed genes
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25. Goncharuk, V.N., Ross, J.S. & Carlson, J.A. Actinbinding protein fascin expression in skin neoplasia.
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26. Hu, W. et al. Increased expression of fascin, motility associated protein, in cell cultures derived from ovarian cancer
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S. Phosphorylation of human fascin inhibits its actin
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32. Adams, J.C. & Schwartz, M.A. Stimulation of fascin
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33. Jawhari, A.U. et al. Fascin, an actin-bundling protein,
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34. Shonukan, O., Bagayogo, I., McCrea, P., Chao, M. &
Hempstead, B. Neurotrophin-induced melanoma cell
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Controlled Release Systems for
Non-Viral Vectors
Lonnie D. Shea and Angela K. Pannier
Lonnie Shea, PhD, is an Assistant Professor of Chemical and
Biological Engineering at Northwestern University’s
McCormick School of Engineering and Applied Science.
Professor Shea is a member of the Cancer Center’s
Tumor Invasion, Metastasis and Angiogenesis Program.
Angela K. Pannier is a graduate student in the
Interdepartmental Biological Sciences Program
at Northwestern University.
A
dapting controlled release technologies to
the delivery of non-viral vectors has the
potential to overcome barriers that limit gene
therapy. Controlled release systems can enhance
gene delivery and increase the extent and duration of transgene expression relative to more
traditional delivery methods. Delivery vehicles
for controlled release are fabricated from natural
and synthetic polymers, which function either
by releasing the vector into the local tissue environment or by maintaining the vector at the
polymer surface. Vector release or binding is
regulated by the effective affinity of the vector
for the polymer, which depends upon the
strength of molecular interactions. These interactions occur through non-specific binding
based on vector and polymer composition or
through the incorporation of complementary
binding sites (e.g., biotin-avidin). This review
examines the delivery of non-viral vectors from
natural and synthetic polymers, and presents
opportunities for continuing developments
to increase their applicability.
Introduction
Controlled release systems for low molecular
weight drugs and proteins have become a multibillion dollar industry, with products such as
35
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Nutropin® Depot, Gliadel® wafer, Norplant,
and CYPHER™ Stent. These systems illustrate
the potential advantages of controlled release,
which include: (1) maintained drug levels
within a desirable range, (2) localized delivery
to a target tissue or cell type to avoid adverse
side effects, (3) decreased dose or number of
dosages, and (4) facilitated delivery for fragile
compounds (i.e., short half-lives). The adaptation of controlled release technologies to the
delivery of non-viral vectors has the potential
to overcome barriers that limit gene therapy.
Controlled release can maintain elevated DNA
concentrations in the cellular microenvironment,
which improves gene delivery1. Additionally,
non-viral vectors may have a relatively short
half-life2, and delivery vehicles can either prevent
their degradation or provide a sustained release.
This review examines gene delivery from
biomaterials and discusses how continuing
advances will increase their applicability.
Delivery mechanisms
Controlled release systems typically employ
polymeric biomaterials that deliver vectors
according to two general mechanisms: i) polymeric release in which the DNA is released from
the polymer or ii) substrate-mediated in which
DNA is retained at the surface. For polymeric
release, DNA is entrapped within the material
and released into the environment, with release
typically occurring through a combination of
diffusion and polymer degradation. Polymeric
delivery may enhance gene transfer by first
protecting DNA from degradation, and then
maintaining the vector at effective concentrations, extending the opportunity for
internalization. DNA release into the tissue can
occur rapidly, as in bolus delivery, or extend
over days to months3-5. Conversely, substratemediated delivery, also termed solid phase
delivery, describes the immobilization of DNA
to a biomaterial or extracellular matrix, which
functions to support cell adhesion and places
DNA directly in the cellular microenvironment.
Cells cultured on the substrate can internalize
36
the DNA either directly from the surface, or by
degrading the linkage between the vector and
the material6.
Vehicle formulations
Vehicles for gene delivery can be fabricated
from both natural and synthetic polymers and
processed into a variety of forms, including
nanospheres, microspheres, or scaffolds.
Nanospheres are particles with diameters ranging from approximately 50 nm to 700 nm7,
consistent with the size of non-viral vectors.
Nanoparticles are internalized and release DNA
intracellularly. In contrast, microspheres with
diameters ranging from 2 µm to 100 µm, are
not readily internalized, but retained within
the tissue to release DNA8,9. Released DNA
can transfect cells at the delivery site, with the
protein product acting locally or distributed
systemically9,10. Alternatively, polymeric scaffolds
function to define a three-dimensional space and
can either be implanted or designed to solidify
upon injection. These scaffolds can deliver DNA
to cells within the surrounding tissue, or can
target those infiltrating the scaffold5,10.
A variety of natural and synthetic materials have
been employed for DNA delivery, which can
be categorized as either hydrophobic (e.g.,
poly(lactide-co-glycolide) (PLG), polyanhydrides) or hydrophilic polymers (e.g., hyaluronic
acid (HA), collagen, poly(ethylene glycol)
(PEG)). Synthetic polymers such as PLG and
polyanhydrides have been widely used in drug
delivery applications, as they are biocompatible
and available in a range of copolymer ratios to
control their degradation. Drug release from
these polymers typically occurs through a
combination of surface desorption, drug diffusion, and polymer degradation11. Alternatively,
hydrogels, which are often more than 98%
water and maintain the activity of encapsulated
vectors, released DNA by diffusion from the
polymer network4, which can be controlled
by crosslinking the polymer12.
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Naked DNA
SHUFHQWRILQFRUSRUDWHG
&XPXODWLYH'1$UHOHDVH
Naked DNA delivery by traditional mechanisms
generally results in low but sustained expression
in vivo, which is limited by poor uptake due
to factors such as degradation and clearance.
Physical (e.g., ultrasound, hydrodynamic injection) and chemical (e.g., cationic lipids/
polymers) methods are continually being
improved to enhance cellular uptake of naked
DNA by altering cell permeability or enhancing
cellular interactions13. Nevertheless, polymeric
delivery represents an alternative approach that
can increase residence time within the tissue
and protect against degradation.
7LPHGD\V
Figure 1. Range of release rates of DNA from PLG scaffolds
achieved through variations in the fabrication process.
Reprinted from the Journal of Controlled Release, Vol. 93 (1), Jang and Shea,
“Controlled Release Systems for….”, 2 Figures only, pp. 69-84. Copyright
(2003), with permission from Elsevier.
Naked DNA interacts weakly with many polymers, leading to release from the vehicle with
rates modulated by the polymer properties.
Collagen based materials released naked DNA
in vitro for times ranging from hours to days4,14,
yet intramuscular implantation of collagen
pellets maintained the DNA locally for 60
days15. HA-based hydrogels also release the
DNA; however, the rate of release can be
controlled by the extent of crosslinking12,16. For
synthetic polymers such as PLG, the integrity of
the DNA can be affected by degradation of the
polymer to lactic acid and glycolic acid5. PLG
polymers can provide release rates ranging from
a few days to more than 60 days (Figure 1),
with the fabrication method and the polymer
composition regulating release15,17,18. Ethylene
vinyl-co-acetate (EVAc) polymers can similarly
provide a sustained release of DNA on the time
scale of weeks19.
DNA releasing polymers administered to multiple sites in vivo have demonstrated the capacity
to transfect cells locally and promote sustained
protein production. An injectable PLG formulation delivered subcutaneously led to 28 days of
expression with 50 µg of DNA17. An implantable
PLG scaffold delivering 500 µg of DNA was
able to transfect cells within and adjacent to the
scaffold, and promote physiological responses5.
Collagen minipellets containing 50 µg of DNA
administered intramuscularly elicited systemic
effects for at least 60 days, which was significantly longer than direct DNA injection9.
DNA Complexes
Although naked DNA provides transfection
in vivo, packaging DNA with cationic lipids
or polymers can enhance in vivo transfection.
Complexes of naked DNA with cationic polymers or lipids facilitate cellular internalization,
by creating a less negative surface charge and
providing stability against degradation20. The
presence of complexation agents can also maintain the stability of DNA complexes during
polymer processing21, and in some cases increase
encapsulation efficiency22. Porous PLG or collagen scaffolds with encapsulated polyplexes or
lipoplexes achieved substantial transfection
in vitro4,23 and in vivo4, but with significantly
altered release profiles compared to naked
DNA, due to interactions of the complexation
reagents with the biomaterial or with adsorbed
serum components24.
Interactions between complexation agents and
the polymer have been adapted to specifically
immobilize DNA complexes to a substrate.
Poly(L-lysine) (PLL) and PEI were modified
with biotin residues for subsequent complexation with DNA and binding to a neutravidin
substrate6,25. Complexes were formed with
37
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Page 38
mixtures of biotinylated and non-biotinylated
cationic polymer at a constant N/P ratio. For
complexes formed with PLL, the number of
biotin groups and their distribution among
the cationic polymer were critical determinants
of both binding and transfection (Figure 2).
Increasing the number of biotin groups per
complex led to increased binding6. However,
transfection was maximal when complexes
2
DNA Density (µg/cm
.%
2
)
DNA Density ( µg/cm )
A
.%
No Tethers
Applications
. .
RLU/mg protein
B
7 10
6
6 10
6
5 10
6
K214-B(12.9)
4 10
6
No Tethers
3 10
6
K214-B(3.8)
2 10 6
1 10 6
0 10 0
(1276) (4022)
100:0
(64)
(201)
5:95
Ratio of Biotinylated
(0)
0:100
K214 (NA)
(0)
(0)
0:100
K19 (NA)
0:100
K19 (TCP)
to Non-Biotinylated Polylysine
Figure 2. Density and transfection of substrate associated
DNA/polylysine complexes formed with varying biotin distribution. (A) DNA density and (B) transgene expression for
complexes formed at a charge ratio of 5.5:1. The notation
K214-B indicates that polylysine (K) has 214 monomers on average and is biotinylated (B), with the number of biotin residues
per polylysine following. The numbers in parentheses below each
bar represent the average moles of biotin per mole of DNA. The
data is presented as the average ± the standard deviation and
the symbol * indicates statistical significance at a level of p
<0.05 for the comparisons indicated. p values were obtained
using the student t test with the single comparisons. The label
NA and TCP indicates the substrate was neutravidin and tissue
culture polystyrene respectively.
Reprinted from the Journal of Controlled Release, Vol. 93 (1), Jang and Shea,
“Controlled Release Systems for….”, 2 Figures only, pp. 69-84. Copyright
(2003), with permission from Elsevier.
contained biotin residues attached to a small
fraction of the cationic polymers25. At this
condition, less than 100 ng of immobilized
DNA mediated transfection, which was
increased 100 fold relative to bolus delivery
38
of similar complexes6. For complexes formed
with PEI, substantial transfection was observed,
but was independent of the number of biotin
groups present on the complex, which suggests
that complex binding occurred by non-specific
interactions with the substrate25. Other systems
have used non-specific binding to mediate
delivery. PLGA and collagen membranes were
coated with phosphatidyl glycerol (1-5%) to
support binding of complexes formed with
polyamidoamine (PAMAM) dendrimers26.
In vivo studies demonstrated a six to eight-fold
enhancement in transfection relative to naked
DNA delivery.
Gene Therapy: Numerous clinical trials have been
completed or are pending for a multitude of
pathologies including malignancy (e.g., colorectal, bladder, and brain). Most trials have
not shown significant therapeutic efficacy or
clinically useful responses, likely due in part to
inefficient gene transfer27,28. Polymeric-based
gene delivery systems may enhance delivery of
the vector and extend the duration of transgene
expression to achieve sufficient protein quantities
that act locally or systemically. For example, IL-2,
IL-12, and TNF-α expression induced by a DNA
releasing gelatin sponge inhibited tumor growth
in heterotopic nodules of tumor bearing mice29.
Functional Genomics: Transfected cell arrays
represent a high throughput approach to
correlate gene expression with functional
cell responses, based on gene delivery from
a surface30. In principle, this system can be
employed for numerous studies, such as screening large collections of cDNAs30 or targets for
therapeutic intervention. Transfected cell arrays
were formed using a substrate-mediated
approach in which plasmids or adenoviruses
were mixed with collagen and spotted onto
glass slides or into wells30,31. Plated cells were
transfected and could be analyzed for cellular
responses using a variety of imaging or
biochemical techniques.
85898 NUMS Journal
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Page 39
Conclusions
In comparison to traditional gene delivery
systems, controlled release can enhance gene
delivery by increasing the extent and duration
of transgene expression, while reducing the
need for multiple interventions. These polymerbased gene delivery systems capitalize on both
specific and non-specific interactions between
the biomaterial and vector, to achieve either
release into the extracellular space or immobilization at the surface. While the potential to
use these polymeric systems has been established, the design parameters by which to
optimize or control gene transfer are not well
understood. Vector and biomaterial development, combined with studies that correlate
system properties (e.g., dose, release rate) with
the extent of transgene expression (i.e., quantity
and duration of protein produced, location of
transgene expression) will lead to molecular
scale design of delivery systems. The development of these systems may increase the efficacy
within current gene therapy trials, and may
also extend the applicability of gene delivery
to other areas such as functional genomics.
Acknowledgments
We would like to thank Tatiana Segura, Zain
Bengali, and Tiffany Houchin for their critical
evaluation of the manuscript. Support was
provided by the Specialized Program of
Research Excellence (SPORE) in Breast Cancer
P50-CA89018) and NSF (BES0092701 (LDS),
Graduate Fellowship (AKP)).
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1. D. Luo, W. M. Saltzman, Nat Biotechnol 18, 893-5.
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2. M. Ogris, S. Brunner, S. Schuller, R. Kircheis, E. Wagner,
Gene Ther 6, 595-605 (Apr, 1999).
3. T. Ochiya, S. Nagahara, A. Sano, H. Itoh, M. Terada,
Curr Gene Ther 1, 31-52 (May, 2001).
4. F. Scherer, U. Schillinger, U. Putz, A. Stemberger,
C. Plank, J Gene Med 4, 634-43 (Nov-Dec, 2002).
5. L. D. Shea, E. Smiley, J. Bonadio, D. J. Mooney, Nat
Biotechnol 17, 551-4 (Jun, 1999).
6. T. Segura, L. D. Shea, Bioconjug Chem 13, 621-9
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8. E. Mathiowitz et al., Nature 386, 410-4 (Mar 27, 1997).
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18. J. H. Jang, L. D. Shea, Journal of Controlled Release 86,
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27. D. Kerr, Nat Rev Cancer 3, 615-22 (Aug, 2003).
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39
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Quality of Life Impact of Early
Radiation Treatment for Breast Cancer
Deborah Dobrez, William Small, Jr., Matthew
Callahan, Krystyna Kiel and Emily Welshman
This study was funded by a grant from the
Drug Information Association
Deborah Dobrez, PhD, is a Research Scientist at Evanston
Northwestern Healthcare, and a Research Assistant Professor at
Dr. Dobrez is a member of the Cancer Center’s
Cancer Control Program.
William Small Jr., MD, is an Associate Professor of Clinical
Radiology, Division of Radiation Oncology. Dr. Small is a
member of the Cancer Center’s Cancer Control Program.
Matthew Callahan, BS, is a Project Coordinator at the
Institute for Health Services Research and Policy Studies
at Northwestern University’s Feinberg School of Medicine.
Emily Welshman, MSW, is a research Project Manager at
Krystyna Kiel, MD, is an Assistant Professor of Radiology
at Northwestern University. She is on the board of the
Illinois and Chicago Divisions of the American Cancer
Society and a medical advisor to the Y-Me Organization
for Cancer Information and Resources. (Not pictured)
40
I
mprovements in oncology treatment are
increasingly focused on reducing patient
burden in terms of side effects, convenience, and
personal cost, in addition to traditional concerns
of tumor response and survival. Evaluation of
the importance of such advances requires measurement of patient preference and tolerance for
side effects of treatment. Partial breast radiotherapy may be a treatment modality that offers
tumor control similar to traditional breast radiotherapy while reducing the burden of therapy. In
our study, we evaluated patient-reported quality
of life for women early in their radiation treatment for breast cancer. Our study demonstrates
the varied sensitivity to change of multiple
quality of life measures, and identifies the early
quality of life impact of radiation treatment.
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Background
In early stage breast cancer, the use of lumpectomy combined with radiotherapy is a standard
form of therapy1. Traditional breast radiotherapy includes 5-7 weeks of daily radiation. The
target of the radiotherapy traditionally includes
the entire breast. It has been known for some
time that the majority of recurrences after
lumpectomy occur in the region of the lumpectomy cavity2. There is increasing data that
radiotherapy delivered only to the lumpectomy
cavity may offer similar control rates as
traditional radiotherapy3. The more limited
radiotherapy can be delivered in only 10 treatments over one week. Therefore, partial breast
radiotherapy may offer reduced toxicity related
to the smaller radiotherapy field and possibly
improved quality of life (QoL).
Patients report a wide range of toxicities related
to radiation treatment. Potential physical side
effects, both acute and persisting, commonly
include irritation of the skin of the breast, breast
pain, lymphedema, radiation dermatitis, pneumonitis, cardiac damage and fatigue. Patients
reported varied emotional responses during
radiation therapy, including tension, loneliness,
nervousness, anxiety, and/or depression4-12. A
wide range of instruments are used to measure
quality of life. Some measures focus on specific
factors such as pain (Modified Post-operative
Pain Questionnaire, Pain Disability Index,
McGill Pain Questionnaire) and mental health
(Mental Health Inventory), while others capture
multi-dimensional aspects of patient well-being
(Functional Assessment of Cancer Therapy
and the European Organization for Research
and Treatment of Cancer Quality of Life
Questionnaire). Comparative studies have
further demonstrated the adverse impact of radiation therapy on quality of life. Quality of life
declines over the course of radiation therapy5,13
(measured by the Quality of Life Index, a 5-item
questionnaire, Dow & Lafferty; and a modified
version of the Breast Cancer Chemotherapy
Questionnaire, Whelan et al.) even as it
improves in women with lumpectomy alone5.
Each of the published studies has relied on
quality of life measures that query patients
about the presence and severity of specific side
effects or aspects of patient well-being. Still
broader measures of quality of life allow patients
to consider all aspects of their health and wellbeing, and to weight these factors in accordance
with their own preferences. One approach to
measuring quality of life is to assess a subject’s
utility, or “satisfaction” for their current health.
Utilities are preference-based measures of quality of life that range from 0 (current health is
equivalent in value to death) to 1 (current
health is equivalent in value to perfect health).
These measures are commonly used to weight
survival in cost-effectiveness studies. For example, 10 years spent in perfect health is equal to
10 quality-adjusted life years, but only 5 quality-adjusted life years if the utility of that time
was equal to 0.5.
Many methods exist and are commonly used for
assessing utilities, including a standard gamble
instrument14, and a time trade-off instrument14,15.
The standard gamble has a sound basis in
expected utility theory, the accepted normative
theory of choice14-16. The standard gamble (SG)
includes a feature of risk-taking, which is inherent in all medical decision-making. Participants
consider a choice between staying in their
current health for the rest of their lives (or staying in some described hypothetical health state),
or undergoing an imaginary treatment with no
side effects that would restore them to perfect
health, but carries with it a stated risk of immediate death. The time trade-off (TTO) method
of assessing utility scores was developed by
Torrance and his colleagues specifically for utility assessment in health care15. Rather than
asking respondents to consider choices with
immediate outcomes, participants are asked
whether they would be willing to trade time to
attain perfect health. For example, in a typical
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TTO interview, participants may be asked what
proportion of a year spent in perfect health
is equivalent to a year spent in the described
hypothetical health state. The length of time
may be constant across all respondents, or may
be life expectancy-adjusted. Many alternatives
exist to the standard gamble and time trade-off
instruments. A visual analog scale is often used,
which simply asks respondents to rate their
overall quality of health on a linear scale. Also,
significant effort has gone into preference-rated
(or weighted) instruments for assessing current
health utility scores, such as the Quality of
Well-Being index17, Euroqol18 and Health
Utilities Index19. Each asks a series of health
status questions, and then converts the health
status score to a utility score, based on scoring
systems derived from community evaluations
of hypothetical health states.
Taking quality of life into account, past studies
have evaluated the relative cost-effectiveness of
radiation therapy when compared with other
medical interventions. Using a Markov model,
Hayman et al.12, compared the strategy conservative surgery (CS) with or without radiation
therapy (RT). Using the standard gamble utility
measure, both breast cancer patients treated
with lumpectomy followed by RT, and medical
oncology nurses rated five different health states
related to breast cancer treatment, on a scale
that ranged from 0 (equivalent to death) to
1 (perfect health). Utility scores ranged from
0.81 (CS alone with an isolated local recurrence
salvaged with mastectomy and reconstructive
surgery) to 0.92 (CS and RT without local or
distant recurrence). They found that the addition of RT resulted in a $9,800 per patient cost
increase, and an increase of 0.35 quality adjusted
life years (QALYs), an incremental cost effectiveness ratio of $28,000/QALY, which was
cost effective compared with other accepted
medical interventions. In an earlier study, using
the same utility scores elicited of breast cancer
patients and medical oncology nurses cited
above, Hayman et al. found that both fear of
42
local future recurrence and actual recurrence
leading to mastectomy have such a detrimental
impact on QoL that patients are willing to
accept the risks and inconvenience of RT to
avoid them20. The investigators concluded that
early-stage breast cancer patients who valued
breast preservation rated the benefits of RT
after breast- conserving surgery to outweigh
both the risks of RT and its potential negative
impact on quality of life. While one of these
studies modeled the cost effectiveness of radiation therapy and the other demonstrated patient
preference for treatment, a full understanding
of the overall QoL impact of radiation therapy
is required using a preference-based measure for
the calculation of its cost-effectiveness relative
to alternative therapies.
Methods
Breast cancer patients undergoing radiation
treatment at Northwestern Memorial Hospital
were recruited for participation in the study. All
patients receiving radiation treatment for breast
cancer were considered eligible. After obtaining
informed consent, a baseline interview was
conducted with each patient following either
her 3rd, 4th or 5th radiation treatment (week
1), with a follow up interview after either her
8th, 9th or 10th radiation treatment (week 2).
During both interviews, participants completed
the patient-rated Eastern Cooperative Oncology
Group (ECOG) performance status rating.
Participants were then randomized to one of
two groups, which determined the order in
which quality of life surveys were given, which
included the Functional Assessment of Cancer
Therapy – Breast (FACT-B). The FACT-B is a
well-established multidimensional QOL instrument21,22. Patients also completed standard
gamble and time trade-off utility questionnaires
at both assessments.
Multiple outcome measures were used to
describe different aspects of patient quality of
life. The TTO and SG questionnaires provide
preference-based measures of patient utility.
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The FACT-B was summarized in to 5 measures:
physical, functional, emotional and social/family
well-being, plus the breast cancer subscale,
which assesses specific symptoms and concerns
of women diagnosed and treated for breast
cancer. The ECOG performance score was
used as a primary measure of patient function.
Descriptive analyses were conducted to characterize quality of life during the first 2 weeks of
radiation treatment. Changes in quality of life
were modeled using a linear regression model,
to determine whether patient characteristics
(baseline function, age and living arrangements)
could predict improvement or worsening of
quality of life, early in radiation treatment. All
statistical analyses were conducted at the α =
0.10 level.
Figure 1. ECOG Performance Status Scores at Weeks 1 and 2
No change in QOL was detected by the four
domains of the FACT-B (physical, functional,
emotional, and social/family well-being; p >
0.10). However, improvement was documented
by the breast cancer subscale (from 25.31 to
26.39, p < 0.01) and both utility measures
(p < 0.01; Figure 2).
Results
A total of sixty-nine patients completed both
the baseline and follow-up interviews. The
patients ranged in age from 26 to 83 years
(mean = 54 years), and were primarily insured
privately (fee for service or preferred provider
organization). Quality of life at baseline varied
considerably across all study measures. Table 1
summarizes baseline measures of function and
quality of life.
Mean (Median) Std Dev Min/Max
ECOG Perf Status
0.362 (0)
0.615
0/2
Standard Gamble
0.937 (0.988)
0.098
0.45/1.00
Time Trade-Off
.934 (0.988)
0.082
0.65/1.00
Physical WB
24.920 (26)
3.666
11/28
Functional WB
22.362 (24)
5.228
1/28
Emotional WB
19.739 (20)
3.599
10/24
Social/Family WB
23.829 (25)
5.663
0/28
25.265 (25.875)
6.648
1.125/36
Breast Cancer
Concerns
Table 1: Week 1 QOL Measures
Patient function declined between week 1 and
2, as measured by the patient-reported ECOG
performance status (Figure 1; p < 0.001).
Figure 2. Mean Utility Scores at Weeks 1 and 2
Multiple regression models were conducted to
determine predictors of improvement in QOL
between weeks 1 and 2. Statistically significant
predictors of change differed across the 3
models. Improvement in standard gamble
scores was weakly related to higher baseline
ECOG performance status (no symptoms
relative to some bed rest) while improvement
in breast cancer subscale scores was more
substantially related to lower baseline ECOG
performance status (some symptoms relative
to none). Improvement in time trade-off scores
was related to the presence of other adults in
the home (a measure of social support).
43
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Change in Standard
Gamble Score
Change in Time
Trade-Off Score
Change in Breast Cancer
Subscale Score
Coefficient
p-value
Coefficient
p-value
Coefficient
p-value
Age (in years)
0.001
0.132
-0.000
0.773
0.041
0.177
Living with other adults vs. Alone
0.017
0.268
0.035
0.064
.267
0.750
ECOG: Some symptoms vs. Normal
-0.007
0.679
0.019
0.363
2.516
0.009
ECOG: Some bedrest vs. Normal
-0.072
0.010
-0.006
0.858
0.268
0.855
R2
0.133
0.064
0.121
*Constant not reported
Table 2. Prediction of Change in QOL
Discussion
Our QOL instruments measure QOL in very
different ways. The FACT-B poses specific
questions to the patients about aspects of their
well-being. Four of the subscales are designed
to generalize to all cancer patients, and the fifth
addresses specific concerns for women with
breast cancer. The utility questionnaires ask
patients to think broadly about their overall
quality of life, without delineation of specific
factors of their well-being that might be
affected by cancer or its treatment.
The present study was originally planned as a
small pilot to test the use of multiple quality of
life instruments in a sample of women early in
radiation treatment. Because no medical chart
review data was collected, it is not possible to
characterize the clinical status of the patients
in our study. Clinical indicators including stage
of disease, prior treatment, and comorbidities
would be expected to increase the explanatory
power of our models. Although the study
patients represent a diverse group with respect
to age, living arrangements and insurance payor,
they each received care at a single institution.
Our study findings may not be generalizable
to the population of breast cancer patients
receiving radiation treatment.
Our study demonstrated considerable variation
in the quality of life of women early in radiation
treatment for breast cancer. Using multiple QOL
instruments, we found seemingly contradictory
results – worsening in ECOG performance
44
status with either no change or improvement in
quality of life – between the first two weeks of
treatment. Both measures of utility, the standard gamble and time trade-off, documented
small (less than one third of a standard deviation) improvements in overall quality of life.
Although these improvements were statistically
significant, they are unlikely to be judged clinically important. The improvements in quality
of life were generally not well-predicted by
baseline characteristics of the patients. Breast
cancer subscale scores also improved, though
again by a small amount.
However, the finding that patient-reported
quality of life did not worsen early in radiation
treatment, even as ECOG performance status
did, suggests that there may be little or no
adverse affect of radiation treatment on
patients’ quality of life. Statistically significant
improvements in symptoms identified by the
breast cancer subscale included swollen arms,
bother from hair loss, and bother from change
in weight. It is likely (though not tested in this
study) that improvements in quality of life indicate an adjustment in expectations of treatment
effects by the patients, rather than a true
reduction in symptoms.
Currently there is significant interest in accelerated partial breast radiotherapy (PBRT). PBRT
can be delivered with brachytherapy or external
beam radiotherapy. Brachytherapy involves an
invasive procedure to place needles or a balloon
catheter into the area of the lumpectomy.
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Radiotherapy in PBRT is generally delivered two
times per day for one week. It has been thought
that treatment delivered rapidly over one week
would be convenient and therefore have the
potential to improve overall QoL. This current
study found a small improvement in QoL during
the second week of standard breast radiotherapy.
In addition, when brachytherapy is utilized for
PBRT there may be a further decrement in QoL
given the invasiveness of the procedure. As we
move forward in the use of PBRT it is important
to prospectively measure QoL in addition to
standard toxicity and efficacy.
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16. Von Neumann, J. and O. Morgenstern, Theory of games
and economic behavior. 3d ed. 1953, Princeton,: Princeton
University Press. 641.
17. Kaplan, R.M. and J.P. Anderson, A general health policy
model: update and applications. Health Services Research,
1988. 23(2): p. 203-35.
18. Kind, P., The EuroQoL Instrument: An Index of health
related quality of life, in Quality of Life and
Pharmacoeconomics in Clinical Trials, B. Spilker, Editor.
1996, Lippincott-Raven: Philadelphia. p. 191-202.
19. Feeny, D., G.W. Torrance, and W. Furlong, Health
Utilities Index, in Quality of Life and Pharmacoeconomics
in Clinical Trials, B. Spilker, Editor. 1996, LippincottRaven Publishers: Philadelphia. p. 239-252.
20. Hayman, J.A., et al., Patient preferences concerning the
trade-off between the risks and benefits of routine radiation
therapy after conservative surgery for early-stage breast
cancer. Journal of Clinical Oncology, 1997. 15(3):
p. 1252-60.
21. Cella, D.F., et al., The Functional Assessment of Cancer
Therapy scale: development and validation of the general
measure. Journal of Clinical Oncology, 1993. 11(3):
p. 570-9.
22. Brady, M.J., et al., Reliability and validity of the
Functional Assessment of Cancer Therapy-Breast qualityof-life instrument. Journal of Clinical Oncology, 1997.
15(3): p. 974-86.
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Shared Research Core Facilities
T
he Robert H. Lurie Comprehensive Cancer
Center of Northwestern University funds
18 shared facilities and resources that provide
services, equipment and expertise that are
fundamental to understanding the basic biology
and clinical manifestations of cancer. These facilities and resources are accessible to all of the
members of the Cancer Center and support
the Cancer Center’s mission to foster basic and
translational research in the mechanisms and
treatment of cancer. To find out more information about the Shared Research Core
Facilities, visit the Cancer Center’s Web site
at http://www.cancer.northwestern.edu/
research.cfm. Two of the 18 Shared Research
Core Facilities are highlighted below.
Pathology Core Facility
The Pathology Core Facility of the Robert H.
Lurie Comprehensive Cancer Center of
Northwestern University has three main
components: research histology, specimen
procurement and oversight of clinical trials.
The research histology component provides all
of the tissue processing and histology services
typically performed in a clinical laboratory but
it is specifically dedicated to the needs of the
46
Northwestern University research community
in general and the Cancer Center research
community in particular. The Pathology Core
Facility is unique in that it has the capability
and flexibility to address specific research
protocol needs.
The tissue procurement component of the
Pathology Core Facility has two main functions
– human tissue and fluid procurement, storage
and distribution and quality assurance and
protection of research subjects. The facility
is directed by Michael R. Pins, MD. You can
reach him via phone (312) 908-9595 or via
email [email protected].
Flow Cytometry Core Facility
The Flow Cytometry Core Facility of the
of Northwestern University provides comprehensive flow cytometry and cell sorting
services for investigators of the Cancer Center,
Northwestern University’s Feinberg School of
Medicine, Northwestern University and other
affiliated institutions. In addition to providing
access to routine flow cytometry assays such
as immunophenotyping and DNA analysis,
the facility provides the guidance, technical
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assistance, and equipment for investigators to
utilize more complex multi-parametric, multilaser measurements as well as cell sorting in
their research. Thus, the Flow Cytometry Core
Facility serves as a focus for individuals interested in cellular based measurements and
cellular heterogeneity in disease.
Services provided by the facility personnel
extend from consultation on experimental
design, sample preparation and data analysis
to instrument operation and set-up for cellsorting and multi-laser operation. The facility
is directed by Charles Goolsby, PhD. You can
reach him via phone (312) 908-1294 or via
email [email protected]. In addition,
you may contact Jeff Nelson, technologist at
[email protected] or Mary Paniagua,
manager at [email protected].
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Selected Member Abstracts
June 2003 - December 2003
Bernard DJ, Burns KH, Haupt B, Matzuk MM
and Woodruff TK
Normal Reproductive Function in InhBP/
p120-Deficient Mice. Molecular and Cellular
Biology, Vol. 23, No. 14: pp.4882-4891, July
2003 (reprinted with permission from the
American Society for Microbiology).
The inhibins are gonadal transforming growth
factor β superfamily protein hormones that
suppress pituitary follicle-stimulating hormone
(FSH) synthesis. Recently, betaglycan and
inhibin binding protein (InhBP/p120, also
known as the product of immunoglobulin
superfamily gene 1 [IGSF1]) were identified as
candidate inhibin coreceptors, shedding light on
the molecular basis of how inhibins may affect
target cells. Activins, which are structurally
related to the inhibins, act within the pituitary
to stimulate FSH production. Betaglycan
increases the affinity of inhibins for the activin
type IIA (ACVR2) receptor, thereby blocking
activin binding and signaling through this
receptor. InhBP/p120 may not directly bind
inhibins but may interact with the activin type
IB receptor, ALK4, and participate in inhibin
B’s antagonism of activin signaling. To better
understand the in vivo functions of InhBP/p120,
48
we characterized the InhBP/p120 mRNAs
and gene in mice and generated InhBP/p120
mutant mice by gene targeting in embryonic
stem cells. InhBP/p120 mutant male and
female mice were viable and fertile. Moreover,
they showed no alterations in FSH synthesis
or secretion or in ovarian or testicular function.
These data contribute to a growing body of
evidence indicating that InhB/p120 does not
play an essential role in inhibin biology.
Bhattacharyya RS and Stern PH
IGF-1 and MAP Kinase Involvement in the
Stimulatory Effects of LNCaP Prostate Cancer
Cell Conditioned Media on Cell Proliferation
and Protein Synthesis in MC3T3-E1
Osteoblastic Cells. Journal of Cellular
Biochemistry, Vol. 90: pp.925-937, October
2003 (this material is used by permission of
Wiley-Liss, Inc., a subsidiary of John Wiley
& Sons, Inc.).
Bone metastases form prostate cancer cause
abnormal new bone formation, however, the
factors involved and the pathways leading to the
response are incompletely defined. We investigated the mechanisms of osteoblast stimulatory
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effects of LNCaP prostate carcinoma cell conditioned media (CM). MC3T3-E1 osteoblastic
cells were cultured with CM from confluent
LNCaP cells. LNCaP CM stimulated MAP
kinase, cell proliferation (3H-thymidine incorporation), and protein synthesis (14C-proline
incorporation) in the MC3T3-E1 cells. The
increases in cell proliferation and protein synthesis were prevented by inhibition of the MAP
kinase pathway. IGF-I mimicked the effects of
the CM on the MC3T3-E1 cells and inhibition
of IGF-I action decreased the LNCaP CM
stimulation of 3H-thymidine and 14C-proline
incorporation and MAP kinase activity. The findings indicate that IGF-I is an important factor for
the stimulatory effects of LNCaP cell CM on cell
proliferation and protein synthesis in osteoblastic
cells, and that MAP kinase is a component of the
signaling pathway for these effects.
Boyapati A, Wilson M, Yu J and Rundell K
SV40 17KT Antigen Complements dnaJ
Mutations in Large T Antigen to Restore
Transformation of Primary Human
Fibroblasts. Virology, Vol. 315 (1): pp.148-158
(2003) (reprinted from Virology – Copyright
2003, with permission from Elsevier).
Tranformation of human cells requires both
SV40 large T and small t antigens. Plasmids
that contained mutations in the amino-terminal
dnaJ domain of the early region fail to transform human diploid fibroblasts. However, large
T dnaJ mutants can be rescued by plasmids that
express early region products other than large
T antigen. The protein found to be responsible
for such complementation was the third early
region product, 17KT. Similar to large T, this
protein reduces levels of the retinoblastomarelated protein, p130, and stimulates cell-cycle
progression of quiescent fibroblasts, two
activities of large T that are disrupted by
dnaJ mutations.
Chatterton RT, Geiger AS, Gann PH and
Khan SA
Formation of Estrone and Estradiol From
Estrone Sulfate by Normal Breast
Parenchymal Tissue. Journal of Steroid
Biochemistry and Molecular Biology, Vol. 86
(2): pp.159-166 (2003) (reprinted from the
Journal of Steroid Biochemistry and Molecular
Biology – Copyright 2003, with permission
from Elsevier).
The study was designed to determine the
process and limitations by which estrone sulfate
may be a precursor of estradiol in the parenchymal cells of the normal breast. The concentration
of estrone sulfate in breast nipple aspirate fluid
was 1000-fold greater than that of estradiol.
Concentrations of 3H-estrone sulfate in
parenchymal ells were only 0.20-0.33 times
that of the 1.0nM concentration in the medium,
while 3H-estrone achieved concentrations
up to 24 times that in the medium at 37ºC.
Nevertheless, estrone sulfate added to the
medium was linearly converted within a 1000fold concentration range to estrone in intact
cells with a mean half-time of conversion of
628 min per 106 cells. Homogenized cells had
a half-time of 246 min per 106 cells. This, the
time for entry of estrone sulfate into cells
reduced the rate by approximately 55%. In split
samples, the vmax values (±S.D.) for intact and
homogenized cells were 12.6 ± 1.4 and 18.3
nmol/h mg DNA, respectively (P<o.o3). The
corresponding km values for intact and homogenized cells were 6.0 ± 1.1 and 4.7 ± 1.0 µM.
Conversion of estrone sulfate to estradiol was
more efficient in intact cells than in homogenates
with mean half-times of 2173 and 7485 min
per 106 cells, respectively. Conversion of estrone
to estrone sulfate did not occur in these cells
despite sulfonation of estrone by MCF-7 breast
cancer cells under identical conditions. It is
concluded that estrone sulfate can serve as a
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precursor for estradiol in normal breast tissue.
Conversion of estrone to estradiol is a limiting
step in the process.
Frater JL, Yaseen NR, Peterson LC, Tallman
MS and Goolsby CL
Biphenotypic Acute Leukemia with
Coexpression of DF79a and Markers of
Myeloid Lineage. Archives of Pathology and
Laboratory Medicine, Vol. 27, No.3: pp.356359 (2003) (reprinted with permission from
the College of American Pathologists).
Acute leukemias demonstrating immunophenotypic features of more than 1 cell lineage are
referred to as acute leukemias of ambiguous
lineage in the new World Health Organization
classification system. A subtype of leukemia
of ambiguous lineage is biphenotypic acute
leukemia in which the malignant cell population
expresses markers of 2 different lineages, most
commonly myeloid and either B- or T-lymphoid
lineages. This entity has been defined by a scoring system proposed by the European Group
for the Immunological Characterization of
Acute Leukemias (EGIL), with various markers
assigned a score of 2, 1, or 0.5 depending on
their specificity for myeloid or lymphoid lineage. Those cases having a score grater than 2
for the myeloid and either the B- or T-lymphoid
lineages are biphenotypic acute leukemia in this
system. One marker, CD79a, has been so clearly
associated with acute lymphoblastic leukemia
(ALL) by some researchers that its expression
in the presence of blast markers is considered
indicative of B-ALL. We describe an unusual
case of acute leukemia meeting the criteria for
biphenotypic acute leukemia in which CD79a
expression was observed in the blast population.
50
Hahn EA, Cella D, Dobrez D, Shiomoto G,
Marcus E, Taylor SG, Vohra M, Chang CH,
Wright BD, Linacre JM, Weiss BD, Valenzuela V,
Chiang HL and Webster K
The Talking Touchscreen: A New Approach
to Outcomes Assessment in Low Literacy.
Psycho-Oncology (2003) (reprinted with
permission from Psycho-Oncology, Copyright
2003, John Wiley & Sons Limited).
Purpose: Cancer patients who are deficient in
literacy skills are particularly vulnerable to experiencing different outcomes due to disparities in
care or barriers to care. Outcomes measurement
in low literacy patients may provide new insight
into problems previously undetected due to the
challenges of completing paper and pencil forms.
Description of study: A multimedia program
was developed to provide a quality of life assessment platform that would be acceptable to
patients with varying literacy skills and computer
experience. One item at a time is presented on
the computer touchscreen, accompanied by a
recorded reading of the question. Various colors,
fonts and graphic images are used to enhance
visibility, and a small picture icon appears near
each text element allowing patients to replay the
sound as many times as they wish. Evaluation
questions are presented to assess patient burden
and preferences.
Results: A ethnically diverse group of 126
cancer patients with a range of literacy skills
and computer experience reported that the
“talking touchscreen” (TT) was easy to use,
and commented on the usefulness of the
multimedia approach.
Clinical implications: The TT is a practical,
user-friendly data acquisition method that
provides greater opportunities to measure
self-reported outcomes in patients with a
range of literacy skills.
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Haynes SA, Huang X, Kambhampati S,
Platanias LC and Bergan RC
p38 MAP Kinase Modulated Smaddependent Changes in Human Prostate Cell
Adhesion. Oncogene, Vol. 22: pp.4841-4850
(2003) (reprinted with permission from Nature,
copyright 2003, Macmillan Publishers Ltd.).
Transforming growth factor beta (TGFβ)
regulates cell adhesion, proliferation, and differentiation in a variety of cells. Smad proteins
are receptor-activated transcription factors that
translocate to the nucleus in response to TGFβ.
We demonstrate here that TGFβ increases cell
adhesion in metastatic PC3-M prostate cancer
cells. TGFβ treatment of PC3-M cells leads to
nuclear translocation of R-Smad proteins. We
show that Smad proteins are necessary, but not
sufficient, for TGFβ-mediated cell adhesion.
After showing that TGFβ upregulated p38
MAP kinase activity in PC3-M cells, we show
that inhibition of p38 MAP kinase partially
blocked TGFβ-mediated increase in cell adhesion, as well as nuclear translocation of Smad3.
Finally, we show that Smad3 is phosphorylated
by p38 MAP kinase in vitro. These findings
implicate crosstalk between the MAP kinase and
Smad signaling pathways in TGFβ’s regulation
of cell adhesion in human prostate cells. This
represents a mechanism by which the pleiotropic
effects of TGFβ may be channeled to modulate
cell adhesion.
Jeruss JS, Sturgis CD, Rademaker AW and
Woodruff TK
Down-Regulation of activin, Activin Receptors
and Smads in High-Grade Breast Cancer.
Cancer Research, Vol. 63: pp.3783-3790, July 1,
2003 (reprinted with permission from the
American Association for Cancer Research).
Activin and transforming growth factor
(TGF)-β, members of the TGF-β superfamily
of growth factors, have been implicated in both
mammary gland development and breast
carcinogenesis. TFG-β is thought to be involved
in the maintenance of mammary gland ductal
architecture and postlactational involution.
TGF-β acts as both a tumor suppressor and
has oncogenic capacities in breast cancer tissue.
Activin is associated with the growth modulation
in glandular organs, and its receptors and signaling proteins are present and regulated during
postnatal mammary gland development, primarily during the lactational phase. The presence of
the major components of the activin signal transduction pathway in different pathologic grades
of breast cancer tissue has not been described
thoroughly, despite evidence from in vitro
studies suggesting that activin can inhibit proliferation in breast cancer-derived cells. On the
basis of the growth regulatory capacity of
activin, we hypothesized that the components of
this signal transduction system would be deregulated as breast cancer becomes more aggressive.
To test this hypothesis, breast cancer samples
were substratified by pathologic grade, a known
prognostic marker for breast cancer, and then
examined for the presence and cellular localization of activin ligand subunits (βA- and βB),
receptors (Act RIIA, Act RIIB, and Act RIB),
and signaling proteins, Smads 2, 3, and 4, by
immunohistochemistry and immunofluorescent
analysis. Breast tissue from healthy patients
undergoing reduction mammoplasty was also
studied. The activin βA-subunit was present in
all of the tissues examined, whereas the βBsubunit, activin type II receptors, and Smads
were less evident in high-grade cancers.
Significant correlations were made in breast
cancer specimens between a decrease in nuclear
Smad 3 abundance and high tumor grade,
high architectural grade, larger tumor size and
hormone receptor negativity. Thus, activin signal
transduction components are present in normal
tissue and grade 1 cancer but down-regulated
in high-grade cancer. The deregulation of this
signal transduction system may be relevant
to advancing oncogenic progression.
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Perry K and Mondragón A
Structure of a Complex Between E. coli DNA
Topoisomerase I and Single-Stranded DNA.
Structure, Vol. 11: pp.1349-1358 (2003)
(reprinted from Structure – Copyright 2003,
with permission from Elsevier).
In order to gain insights into the mechanism of
ssDNA binding and recognition by Escherichia
coli DNA topoisomerase I, the structure of 67
kDa N-terminal fragment of topoisomerase I
was solved in complex with ssDNA. The structure reveals a new conformational stage in the
multistep catalytic cycle of type IA topoisomerases. In the structure, the ssDNA binding
groove leading to the active site is occupied, but
the active site is not fully formed. Large conformational changes are not seen; instead, a single
helix parallel to the ssDNA binding groove
shifts to clamp the ssDNA. The structure helps
clarify the temporal sequence of conformational
events, starting from an initial empty enzyme
and proceeding to a ssDNA-occupied and
catalytically competent active site.
study we have analyzed gene transcription in
primary B cells from LMP2A transgenic mice,
LMP2A-expressing human B-cell lines, and
LMP2A-positive and –negative EBV-infected
lumphoblastoid cell lines (LCLs). We demonstrate that LMP2A increases the expression of
genes associated with cell cycle induction and
inhibition of apoptosis, alters the expression of
genes involved in DNA and RNA metabolism,
and decreases the expression of B-cell-specific
factors and genes associated with immunity.
Furthermore, many alterations in gene expression induced by LMP2A are similar to those
recently described in HRS cells of Hodgkin
lymphoma and activated, proliferating germinal
center centroblasts/centrocytes. These correlations suggest that LMP2A expression in
EBV-infected B cells may lead to the induction
and maintenance of an activated, proliferative
state that could ultimately result in the development of Hodgkin lymphoma.
Staradub VL, Rademaker AW and Morrow M
Factors Influencing Outcomes for Breast
Conservation Therapy of Mammographically
Portis T, Dyck P and Longnecker R
Epstein-Barr Virus (EBV) LMP2A Induces
Alterations in Gene Transcription Similar to
Those Observed in Reed-Sternberg Cells of
Hodgkin Lymphoma. Blood, Vol. 102 (12):
pp. 4166-4178, December 1, 2003 (reprinted
with permission from Blood).
Epstein-Barr virus (EBV) is associated with the
development of a variety of malignancies,
including Hodgkin lymphoma. One of the few
viral transcripts expressed in EBV-positive
Hodgkin/Reed-Sternberg (HRS) cells of
Hodgkin lymphoma is latent membrane protein
2A (LMP2A). This viral protein blocks B-cell
receptor (BCR)-signaling in vitro. Furthermore,
expression of LMP2A in developing B-cells in
vivo induces a global down-regulation of genes
necessary for proper B-cell development. In this
52
Detected Malignancies. Journal of the
American College of Surgeons, Vol. 196(4):
pp.518-524 (2003) (reprinted with permission
from the American College of Surgeons).
Objective: To evaluate the importance of surgeon
caseload, lesion type and biopsy type on
outcomes in breast conservation therapy (BCT).
Background: Breast conservation therapy has
low rates of morbidity and mortality and is
being performed with increasing frequency. Its
primary advantage is cosmetic, and the amount
of breast tissue resected is the main determinant
of cosmetic outcomes.
Study Design: Two hundred seventeen consecutive patients undergoing breast conservation
therapy at Northwestern Memorial Hospital for
mammographically detected breast cancer were
evaluated. The volume of tissue excised was
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compared with the volume of the tumor as a
ratio. Univariate and multivariate analyses of the
relationships between the specimen-to-tumorvolume ratio (STVR) and histologic diagnosis,
biopsy type, surgeon caseload and lesion type
were examined.
Results: The mean (log scale) SVTR was significantly lower when the mammographic lesion
was identified as a mass or architectural distortion versus calcifications (p<0.001 in multivariate
analysis). Mean log (STVR) was also decreased
for higher-caseload surgeons (p=0.02). Core
biopsy before lumpectomy was associated
with significantly increased mean log (STVR)
(83 versus 50, p=0.05) without significantly
increasing the rate of negative margins.
Conclusions: Mammographic lesion type and
biopsy method were associated with the amount
of tissue excised relative to tumor size as measured by STVR. In addition, surgeons with
higher caseloads were better able to perform
needle localization lumpectomy to negative
margins while limiting the volume of normal
breast tissue excised.
Swanson KA, Kang RS, Stamenova SD, Hicke L
and Radhakrishnan I
Solution Structure of Vps27 UIM-ubiquitin
Complex Important for Endosomal Sorting
and Receptor Downregulation. EMBO
Journal, Vol. 22, No. 18: pp. 4597-4606
(2003) (reprinted with the permission from
the EMBO Journal).
Monoubiquitylation is a well-characterized
signal for the internalization and sorting of
integral membrane proteins to distinct cellular
organelles. Recognition and transmission of
monoubiquitin signals is mediated by a variety
of ubiquitin-binding motifs such as UIM, UBA,
UEV, VHS and CUE in endocytic proteins.
The yeast Vps27 protein requires two UIMs
for efficient interactions with ubiquitin and for
sorting cargo into multivesicular bodies. Here
we show that the individual UIMs of Vps27
exist autonomously folded α-helices that bind
ubiquitin independently, noncoorperatively and
with modest affinity. The Vps-27 N-terminal
UIM engages the Leu8-Ile44-Val70 hydrophobic patch of ubiquitin through a helical surface
conserved in UIMs of diverse proteins, including that of the S5a proteasomal regulatory
subunit. The Leu8-Ile44-Val70 ubiquitin
surface is also the site of interaction for CUE
and UBA domains in endocytic proteins,
consistent with the view that ubiquitin-binding
endocytic proteins act serially on the same
monoubiquitylated cargo during transport
from cell surface to the lysosome.
Tsuruta D, Hopkinson SB, Lane KD,
Werner MC, Cryns VL and Jones JCR
Crucial Role of the Specificity-Determining
Loop of the Integrin β4 Subunit in the Binding
of Cells to Laminin-5 and Outside-In Signal
Transduction. Journal of Biological Chemistry,
Vol. 278, No. 40: pp.38707-38714 (2003)
(reprinted with permission from the American
Society for Biochemistry & Molecular Biology).
Within each hemidesmosome, α6β4 integrin
plays a crucial role in hemidesmosome assembly
by binding to laminin-5 in the basement
membrane zone of epithelial tissue.
Recent analyses have implicated “specificitydetermining loops” (SDLs) in the I-like domain
of β integrin in regulating ligand binding. Here,
we investigated the function of an SDL-like
motif within the extracellular I-like domain
of β4 integrin. We generated pint mutations
within the SDL of β4 integrin tagged with green
fluorescent protein (GFP-β4K150A and GFPβ4155L). We also generated a mutation within
the I-like domain of the β4 integrin, lying
outside the SDL region (GFP-β4V284E). We
transfected constructs encoding the mutated β4
integrins and a GFP-conjugated wild type β4
integrin (GFP-β4WT) into 604G cells, which
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assemble hemidesmosomes, and human
endothelial cells, which express little endogenous β4 integrin. In transfected 804G cells,
GFP-β4WT and GFP-β4V284E colocalize
with hemidesmosome proteins, whereas hemidesmosomal components in cells expressing
GFP-β4K150A and GFP-β4Q155L are aberrantly localized. In endothelial cells, GFP-β4WT
and mutant proteins are co-expressed at the
cell surface with α6 integrin. When transfected
endothelial cells are plated onto laminin-5
matrix, GFP-β4K150A and GFP-β4Q155L do
not. GFP-β4WT and GFP-β4V284E expressed
in endothelial cells associate with the adaptor
protein Shc when the cells are stimulated with
laminin-5. However, GFP-β4K150A and GFPβ4Q155L fail to associate with Shc even when
laminin-5 is present, thus impacting downstream signaling. These results provide evidence
that the SDL segment of the β4 integrin subunit
is required for ligand binding and is involved in
outside-in signaling.
Winchester DJ, Bernstein JR, Jeske JM,
Nicholson MH, Hahn EA, Goldschmidt RA,
Watkin WG, Sener SF, Bilimoria MB, Barrera E
and Winchester DP
Updating of Atypical Ductal Hyperplasia
After Vacuum-Assisted 11-Gauge
Stereotactic Core Needle Biopsy. Archives of
Surgery, Vol. 138: pp.619-623 (2003) (reprinted
with permission from the American Medical
Association – Copyright 2003, American
Medical Association. All rights reserved).
Background: Nonpalpable mammographic
abnormalities are frequently evaluated by means
of a stereotactic core needle biopsy. This technique is a very sensitive indicator of invasive
cancer, but is less reliable to discriminate between
ductal carcinoma in situ and atypical ductal
hyperplasia (ADH). The objective of this study
was to determine the correlation of the 11-gauge
vacuum-assisted core needle biopsy to open
biopsy when a diagnosis of ADH is obtained.
54
Hypothesis: The use of 11-gauge vacuumassisted stereotactic core needle biopsy does
not conclusively diagnose ADH.
Design: Retrospective analysis.
Setting: University-affiliated teaching hospital.
Patients: Mammographic findings were evaluated
with an 11-gauge vacuum-assisted stereotactic
core biopsy in 1750 patients. Seventy-seven
patients were diagnosed as having ADH;
of these, 65 underwent excisional biopsy.
Main Outcome Measures: Pathological
upstaging rate.
Results: Of the 65 patients who underwent
excisional breast biopsy, 11 (17%) had their
condition upstaged to a breast cancer diagnosis.
These patients had presented at a later age than
those who retained a benign diagnosis after
excisional biopsy. The number of core taken
did not correlated with diagnostic accuracy.
Conclusions: Of the 65 patients who underwent open biopsy for ADH in this series, only
83% had an accurate diagnosis. A diagnosis of
ADH by stereotactic core needle biopsy should
be followed by an open excisional biopsy.
Xiao W, Zhang Q, Jiang F, Pins M,
Kozlowski JM and Wang Z
Suppression of Prostate Tumor Growth
by U19, a Novel Testosterone-Regulated
Apoptosis Inducer. Cancer Research, Vol. 63:
pp.4698-4704, August 1, 2003 (reprinted with
permission from the American Association for
Cancer Research).
Androgens control prostate homeostasis and
regulated androgen response genes. Here, we
report the identification and characterization of
U19, a novel testosterone-regulated apoptosis
inducer with tumor suppressive activity. U19 is
an evolutionarily conserved protein expressed
in many human tissues, with the most abundant
expression in the prostate, bone marrow, kidney
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and lymph nodes. Overexpression of U19 in
12 surveyed cell lines induced apoptosis, and a
new protein synthesis is required for apoptosis
induction. Expression of U19 in xenograft
prostate tumors markedly induced apoptosis
and inhibited tumor growth in vivo. Consistent
with its tumor-suppressive role, U19 downregulation was observed in all of the surveyed
prostate cancer cell lines and in 19 of 23 clinical
human prostate tumor specimens. Loss of
heterozygosity analysis revealed U19 allelic loss
in 19 of the 23 specimens. Furthermore, two of
the specimens had homozygous U19 deletions,
and one specimen had hypermethylated U19
promoters, indicating that U19 can be inactivated genetically or epigenetically. These
observations suggest that U19 is growth
inhibitory and tumor suppressive and that the
disruption of androgen-dependent growth inhibition via U19 down-regulation is commonly
associated with prostate cancer progression.
Yang Q, Liu S, Tian Y, Salwen HR, Chlenski A,
Weinstein J and Cohn SL
Methylation-Associated Silencing of the
Thrombospondin-1 Gene in Human
Neuroblastoma. Cancer Research, Vol. 63:
pp.6299-6310, October 1, 2003 (reprinted with
permission from the American Association for
Cancer Research).
Tumor angiogenesis, a major requirement for
tumor outgrowth and metastasis, is regulated by
pro- and antiangiogenic factors. Methylationassociated inactivation of the angiogenesis
inhibitor thrombospondin- (TSP-1) has been
observed recently in some adult tumors. To
investigate the role of TSP-1 in pediatric cancer,
we examined its pattern of expression and
mechanism of regulation in neuroblastoma
(NB). TSP-1 was silenced in a subset of undifferentiated, advanced-stage tumors and NB
cell lines. In contrast, most localized tumors
expressed this angiogenesis inhibitor, and a
significant correlation between morphological
evidence of neuroblast differentiation and TSP-1
expression was observed. Luciferase assays
demonstrated the presence of nuclear factors
required for TSP-1 transcription in both TSP-1
positive and-negative cell lines, but no correlation between TSP-1 prompter activity and the
level of TSP-1 mRNA expression was seen. Our
studies indicate that the transcriptional silencing
of TSP-1 was caused by methylation. TSP-1
promoter methylation was detected in all of the
NB cell lines lacking TSP-1 mRNA and in 37%
of the NB clinical tumors analyzed. Furthermore,
treatment with the demethylating agent, 5-Aza2’-deoxycytidine (5-Aza-dC), restored TSP-1
expression in NB cell lines. Disrupting methylation with 5-Aza-dC also led to significant
inhibition of NB in vivo and re-expression
of TSP-1 in a subset of NB xenografts. These
results suggest that 5-Aza-dC inhibits NB
growth by augmenting the expression of TSP-1
along with other genes that suppress tumor
growth. Demethylating agents may prove to
be effective candidates for the treatment of
children with NB.
55
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Selected Bibliography of Publications
by Cancer Center Members
1. Alam M, Caldwell JB and Eliezri YD, Human papillomavirus-associated digital squamous cell carcinoma: literature
review and report of 21 new cases. Journal Am Acad Dermatol
48:385-393, 2003.
2. Ali MY, Oyama Y, Monreal J, Winter JN, Tallman
MS, Williams SF, Singhal S, Gordon LI and Mehta J, Ideal
or actual body weight to calculate CD34+ cell doses for autologous hematopoietic stem cell transplantation? Bone Marrow
Transplantation, 31(10):861-4, 2003.
3. Altman KW, Haines GK, Vakkalanka SK, Keni SP,
Kopp PA and Radosevich JA, Identification of Thyroid
Hormone Receptors in the Human Larynx. Laryngoscope,
Vol 113, pp 1931-1934, 2003.
4. Altman KW, Haines GK, Hammer ND and Radosevich
JA, The H+/K+-ATPase (proton) pump is expressed in
human laryngeal submucosal glands. Laryngoscope, 113(11):
1927-30, 2003.
5. Ang AL, Folsch H, Koivisto UM, Pypaert M and
Mellman I, The Rab8 GTPase selectively regulates AP-1Bdependent basolateral transport in polarized Madin-Darby
canine kidney cells. Journ of Cell Biology, Vol 163, No 2,
pp 339-350, 2003.
6. Angelos P, Lafreniere R, Murphy TF and Rosen W,
Ethical issues in surgical treatment and research. Current
Problems in Surgery, 40(7):353-448, 2003.
7. Angtuaco TL, Oprescu FG, Lal SK, Pennington JH,
Russell BD, Co JM and Howden CW, Universal precautions
guideline: self-reported compliance by gastroenterologists and
gastrointestinal endoscopy nurses—a decade’s lack of progress.
American Journal of Gastroenterology, 98(11):2420-3, 2003.
8. Argiris A, Dutra J, Paraskevi T and Haines K,
Esthesioneuroblastoma: The Northwestern University
Experience, The Laryngoscope, Rhinological and Otological
Society, Inc, 113: 155-160, 2003.
9. Argiris A, Haraf DJ, Kies MS and Vokes EE, Intensive
concurrent chemoradiotherapy for head and neck cancer with
5-Fluorouracil- and hydroxyurea-based regimens: reversing a
pattern of failure. Oncologist 8(4): 350-60, 2003.
56
10. Argiris A, Mellott A and Spies S, PET scan assessment of chemotherapy response in metastatic patients. Am
Journal Clinical Oncology, 26(6): 563-6, 2003.
11. Argiris A, Smith SM, Stenson K, Mittal B, Pelzer
HJ, Kies MS, Haraf DJ and Vokes E, Concurrent chemoradiotherapy for N2 or N3 squamous cell carcinoma of the head
and neck from an occult primary. Annals of Oncology 14:
1306-1311, 2003.
12. Ariztia EV, Subbarao V, Solt DB, Rademaker AW,
Iyer AP and Oltvai ZN, Osteopontin contributes to hepatocyte growth factor-induced tumor growth and metastasis
formation. Experimental Cell Research, Vol 288,
pp 257-267, 2003.
13. Arozullah AM, Parada J, Bennett CL,
Deloria-Knoll M, Chmiel JS, Phan L and Yarnold PR,
A Rapid Staging Sysem for Predicting Mortality From HIVAssociated Community-Acquired Pneumonia. Chest, Vol 123,
No 4, pp 1151-1160, 2003.
14. Avram MJ and Krejcie TC, Using Front-end
Kinetics to Optimize Target-controlled Drug Infusions.
Anesthesiology, Vol 99, No 5, pp 1078-1086, 2003.
15. Bai X, Cerimele F, Ushio-Fukai M, Waqas M,
Campbell PM, Govindarajan B, Der CJ, Battle T, Frank DA,
Ye K, Murad E, Dubiel W, Soff G, Arbiser J and Honokiol,
A small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. Journal of Biological
Chemistry, 278(37):35501-7, 2003.
16. Bailey RC, Nam JM, Mirkin CA and Hupp JT,
Real-time multicolor DNA detection with chemoresponsive
diffraction gratings and nanoparticle probes. Journal of the
American Chemical Society, 125(44):13541-7, 2003.
17. Baker MS, Chen X, Rotramel AR, Nelson JJ, Lu B,
Gerard C, Kanwar Y and Kaufman DB, Genetic deletion of
chemokine receptor CXCR3 or antibody blockade of its ligand
IP-10 modulates posttransplantation graft-site lymphocytic
infiltrates and prolongs functional graft survival in pancreatic
islet allograft recipients. Srg 134(2):126-33, 2003.
85898 NUMS Journal
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18. Balazsi G, Kay KA, Barabasi AL and Oltvai Z,
Spurious spatial periodicity of co-expression in microarray
data due to printing design. Nucleic Acids Research, Vol 31,
No 15, pp 4425-4433, 2003.
19. Baliki M, Al-Amin HA, Atweh SF, Jaber M, Hawwa
N, Jabbur SJ, Apkarian AV and Saade NE, Attenuation of
neuropathic manifestations by local block of the activities of
the ventrolateral orbito-frontal area in the rat. Neuroscience,
120(4):1093-104, 2003.
20. Baluchamy S, Rajabi HN, Thimmapaya R, Navaraj A
and Thimmapaya B, Repression of c-Myc and inhibition of
G1 exit in cells conditionally overexpressing p300 that is not
dependent on its histone acetyltransferase activity. Proceedings
of the National Academy of Sciences of the United States of
America, 100(16):9524-9, 2003.
21. Band V, In vitro models of early neoplastic transformation of human mammary epithelial cells. Methods in
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22. Baronzio G, Freitas I and Kwaan HC, Tumor
Microenvironment and Hemorheological Abnormalities.
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23. Barouch DH, Kunstman J, Glowczwskie J, Kunstman
KJ, Egan MA, Peyerl FW, Santra S, Kuroda MJ, Schmitz JE,
Beaudry K, Krivulka GR, Lifton MA, Gorgone DA,
Wolinsky SM and Letvin NL, Viral escape from dominant
simian immunodeficiency virus epitope-specific cytotoxic T
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24. Barry SM, Zisoulis DG, Neal JW, Clipstone NA and
Kansas GS, Induction of FucT-VII by the Ras/MAP kinase
cascade in Jurkat T cells. Blood, 102(5):1771-8, 2003.
25. Bartelink H, Benz C, Cleveland D, Dorn R,
Gralow J, Gradishar WJ, Grant K, Heimann R, Hellman S,
Hudis C, Kerbel R, Lippman M, Lung J, Posner MC, Steeg P,
Vestal R, Weichselbaum RR and Zetter B, Expedition
Inspiration Fund for Breast Cancer Research Meeting 2003.
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26. Batra PS, Kern RC, Tripathi A, Conley DB, Ditto AM,
Haines GK, Yarnold PR and Grammar L, Outcome analysis
of endoscopic sinus surgery in patients with nasal polyps and
asthma. Laryngoscope, 113(10):1703-6, 2003.
27. Bennett CL and Schumock GT, Cost Analyses
Of Adjunct Colony Stimulating Factors For Older Patients
With Acute Myeloid Leukaemia: Can They Improve
Clinical Decision Making? Drugs Aging, Vol 20, No 7,
pp 479-483, 2003.
28. Bennett CL, Somerfield MR, Pfister DG, Tomori C,
Yakren S and Bach PB, Perspectives on the Value of American
Society of Clinical Oncology Clinical Guidelines as Reported
by Oncologists and Health Maintenance Organizations. Journal
of Clinical Oncology, Vol 21, No 5, pp 937-941, 2003.
29. Bennett JL, Elhofy A, Dal Canto MC, Tani M,
Ransohoff RM and Karpus WJ, CCL2 transgene expression
in the central nervous system directs diffuse infiltration of
CD45 highCD11b+monocytes and enhanced Theiler’s murine
encephalomyelitis virus-induced demyelinating disease. Journal
of NeuroVirology, Vol 9, pp 623-636, 2003.
30. Bentrem D, Fox JE, Pearce ST, Liu H, Pappas S,
Kupfer D, Zapf JW and Jordan VC, Distinct molecular
conformations of the estrogen receptor alpha complex
exploited by environmental estrogens. Cancer Research,
63(21):7490-6, 2003.
31. Bernard DJ, Burns KH, Haupt B, Matzuk MM and
Woodruff TK, Normal reproductive function in InhBP/
p120-deficient mice. Molecular and Cellular Biology, 23(14):
4882-4891, 2003.
32. Berry RW, Abraha A, Lagalwar S, LaPointe N,
Gamblin TC, Cryns VL and Binder LI, Inhibition of tau
polymerization by its carboxy-terminal caspase cleavage
fragment. Biochemistry, Vol 42, pp 8325-8331, 2003.
33. Bhattacharyya RS and Stern PH, IGF-I and MAP
kinase involvement in the stimulatory effects of LNCaP
prostate cancer cell conditioned media on cell proliferation
and protein synthesis in MC3T3-e1 osteoblastic cells. Journal
of Cellular Biochemistry, 90:925-937, 2003.
34. Bian Y, Kaklamani VG, Reich J and Pasche B,
TGF-beta signaling alterations in cancer. Cancer Treatment
& Research, 115:73-94, 2003.
35. Boehm BO, Lang G, Volpert O, Jehle PM,
Kurkhaus A, Rosinger S, Lang GK and Bouck N, Low
content of the natural ocular anti-angiogenic agent pigment
epithelium-derived factor (PEDF) in aqueous humor predicts
progression of diabetic retinopathy. Diabetologia, 46(3):
394-400, 2003.
36. Boyapati A, Wilson M, Yu J and Rundell K, SV40
17KT antigen complements dnaJ mutations in large T antigen
to restore transformation of primary human fibroblasts.
Virology, doi:10,1016/S0042-6822(03)00524-5, 2003.
37. Breen EC, Boscardin WJ, Detels R, Jacobson LP,
Smith MW, O’Brien SJ, Chmiel JS, Rinaldo CR, Lai S
and Martinez-Maza O, Non-Hodgkin’s B cell lymphoma
in persons with acquired immunodeficiency syndrome is
associated with increased serum levels of IL10, or the IL10
promoter -592 C/C genotype. Clinical Immunology,
109(2):119-29, 2003.
38. Breslow NE, Norris R, Norkool PA, Kang T,
Beckwith JB, Perlman EJ, Ritchey ML, Green DM
and Nichols KE, National Wilms Tumor Study Group,
Characteristics and outcomes of children with the Wilms
tumor-Aniridia syndrome: a report from the National Wilms
Tumor Study Group. Journal of Clinical Oncology,
21(24):4579-85, 2003.
39. Brockstein B, Organ preservation for advanced
head and neck cancer concomitant chemoradiation. Cancer
Treatment & Research, 114:235-48, 2003.
40. Budunova IV, Kowalczyk D, Perez P, Yao YJ,
Jorcano JL and Slaga TJ, Glucocorticoid receptor functions as
a potent suppressor of mouse skin carcinogenesis. Oncogene,
Vol 22, pp 3279-3287, 2003.
41. Bulun SE, Ovulation induction in women with
infertility: a new indication for aromatase inhibitors. Fertility
& Sterility, 80(6):1338; discussion 1339, 2003.
42. Bulun SE, Sebastian S, Takayama K, Suzuki T,
Sasano H and Shozu M, The human CYP19 (aromatase
P450) gene: update on physiologic roles and genomic
organization of promoters. Journal of Steroid Biochemistry
& Molecular Biology, 86(3-5):219-24, 2003.
43. Burt RK, Drobyski WR, Seregina T, Traynor A,
Oyama Y, Keever-Taylor C, Stefka J, Kuzel TM, Brush M,
Rodriquez J, Burns W, Tennant L and Link C, Herpes
simplex thymidine kinase gene-transduced donor lymphocyte
infusions. Experimental Hematology, 31(10):903-10, 2003.
57
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44. Calhoun EA and Bennett CL, Evaluating the total
costs of cancer: the Northwestern University costs of cancer
program. Oncology, Vol 17, No 1, pp 109-120, 2003.
45. Calhoun EA, Welshman EE, Chang CH, Lurain JR,
Fishman DA and Cella D, Psychometric evaluation of the
functional assessment of cancer therapy/gynecologic oncology
group-neurotoxicity (FACT/GOG-Ntx) questionnaire for
patients receiving systemic chemotherapy. International
Journal of Gynecological Cancer, 13(6), 741-748, 2003.
46. Cao YC, Jin R, Nam JM, Thaxton CS and
Mirkin CA, Raman dye-labeled nanoparticle probes
for proteins. Journal of the American Chemical Society,
125(48):14676-7, 2003.
47. Cardosi RJ, Cardosi RP, Grendys EC, Fiorica JV
and Hoffman MS, Infectious urinary tract morbidity with
prolonged bladder catheterization after radical hysterectomy.
American Journal of Obstetrics & Gynecology, 189(2):380-3;
discussion 383-4, 2003.
48. Carthew RW, Making and breaking with nucleases
and small RNAs. Nature Structural Biology, 10(10):
776-7, 2003.
49. Catalona WJ, Bartsch G, Rittenhouse HG,
Evans CL, Linton HJ, Amirkhan A, Horninger W, Klocker H
and Mikolajczyk SD, Serum pro prostate specific antigen
improves cancer detection compared to free and complexed
prostate specific antigen in men with prostate specific antigen
2 to 4 ng/ml. Journal of Urology, 170(6 Pt 1):2181-5, 2003.
50. Cella D, Paul D, Yount S, Winn R, Chang CH,
Banik D and Weeks, J, What are the most important symptom
targets when treating advanced cancer? A survey of providers
in the National Comprehensive Cancer Network (NCCN).
Cancer Investigation, 21(4), 526-535, 2003.
51. Cella D, Peterman A, Hudgens S, Webster K and
Socinski MA, Measuring the side effects of taxane therapy in
oncology: the functional assesment of cancer therapy-taxane
(FACT-taxane). Cancer, 98(4):822-31, 2003.
52. Chang CH and Gehlert S, The Washington
Psychosocial Seizure Inventory: Psychometric evaluation and
future applications, seizure. European Journal of Epilepsy,
12(5), 261-267, 2003.
53. Chang CH, Item banking and computerized adaptive
testing in health outcomes assessment. Abstracts of the
International Conference on Health Policy Research,
30-31, 2003.
54. Chang CH and Emanuel LL, Development and
initial validation of a family caregiver burden screening and
assessment instrument (BURDEN). The Gerontologist,
43(S1), 48, 2003.
55. Chang CH and Yang D, Using mobile patientreported outcomes to enhance patient care. Quality of Life
Research, 11(7), 853, 2003.
56. Changela A, Chen K, Xue Y, Holschen J, Outten CE,
O’Halloran TV and Mondragon A, Molecular basis of
metal-ion selectivity and zeptomolar sensitivity by CueR.
Science, Vol 301, pp 1383-1387, 2003.
57. Chapman SC and Woodruff TK, Betaglycan localization in the female rat pituitary: implications for the regulation
of follicle-stimulating hormone by inhibin. Endocrinology,
144(12): 5640-5649, 2003.
58
58. Chatterton RT, Geiger AS, Gann PH and Kahn SA,
Formation of estrone and estradiol from estrone sulfate by
normal breast parenchymal tissue. Journal Steroid Biochem
Mol Biol, 86:159-166, 2003.
59. Chatterton, RT, Geiger AS, Gann PH, Kahn SA,
Quality of life in patients with newly diagnosed chronic phase
chronic myeloid leukemia on imatinib versus results from
the IRIS study. Journal of Clinical Oncology, Vol 21, No 11,
pp 2138-2146, 2003.
60. Chen D, Walsby C, Hoffman BM and Frey PA,
Coordination and mechanism of reversible cleavage of
S-adenosylmethionine by the [4Fe-4S] center in lysine
2,3-aminomutase. Journal of the American Chemical Society,
125(39):11788-9, 2003.
61. Chen X, Kojima S-I, Borisy GG and Green KJ,
p120 catenin associates with kinesin and facilitates the transport of cadherin-catenin complexes to intercellular junctions.
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62. Chenn A and Walsh CA, Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in
beta-catenin overexpressing transgenic mice. Cerebral Cortex,
13(6):599-606, 2003.
63. Cherry AM, Brockman SR, Paternoster SF, Hicks GA,
Neuberg D, Higgins RR, Bennett JM, Greenberg PL, Miller K,
Tallman MS, Rowe J and Dewald GW, Comparison of interphase FISH and metaphase cytogenetics to study myelodysplastic
syndrome: an Eastern Cooperative Oncology Group (ECOG)
study. Leukemia Research, 27(12):1085-90, 2003.
64. Cheson BD, Bennett JM, Kopecky KJ, Buchner T,
Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS,
Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W,
Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R,
Bloomfield CD and LoCocco F, International working group
for diagnosis, standardization of response criteria, treatment
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65. Chilukuri S, Alam M and Goldberg LH, Two atypical
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66. Chiu B CH and Weisenburger DD, An Update of
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67. Chlebowski R, Hendrix SL, Langer RD, Stefanick M,
Gass M, Lane D, Rodabough R, Gilligan MA, Cyr M,
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68. Chlenski A, Liu S and Cohn SL, The regulation
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69. Cleeland CS, Reyes-Gibby CC, Schall M, Nolan K,
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70. Cramer SD, Chang BL, Rao A, Hawkins GA,
Zheng SL, Wade WN, Cooke RT, Thomas LN, Bleecker ER,
Catalona WJ, Sterling DA, Meyers DA, Ohar J and Xu J,
Association between genetic polymorphisms in the prostatespecific antigen gene promoter and serum prostate-specific
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antigen levels. Journal of the National Cancer Institute,
95(14):1044-53, 2003.
71. Dahl T and Veis A, Electrostatic interactions lead to
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72. Dapueto JJ, Francolino C, Servente L, Chang CH,
Gotta I, Levin R and del Carmen Abreu M, Evaluation of the
Functional Assessment of Cancer Therapy- General (FACT-G)
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73. David KM, Cella D, Yount S, Kahn S, Bass M,
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74. Daviglus ML, Liu K, Pirzada A, Yan LL, Garside DB,
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Favorable cardiovascular risk profile in middle age and
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75. Daviglus ML, Liu K, Yan LL, Pirzada A, Garside DB,
Schiffer L, Dyer AR, Greenland P and Stamler J, Body
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76. Dean DA, Electroporation of the vasculature and
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77. Dean DA, Machado-Aranda D, Blair-Parks K,
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78. Deb DK, Sassano A, Lekmine F, Majchrzak B,
Verma A, Kambhampati S, Uddin S, Rahman A, Fish EN
and Plantanias LC, Activation of protein kinase C delta by
IFN-gamma. Journal of Immunology, 171(1):267-73, 2003.
79. DeHart AKA, Schnell JD, Allen DA, Tsai JY and
Hicke L, Receptor Internalization in Yeast Requires the
Tor2-Rho1 Signaling Pathway. Molecular Biology of the
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80. DeHart GW, Healy KE and Jones JCR, The role of
a3B1 integrin in determining the supramolecular organization
of laminin-5 in the extracellular matrix of keratinocytes.
Experimental Cell Research, 283:67-79, 2003.
81. Deonarain R, Verma A, Porter AC, Gewert DR,
Plantanias LC and Fish EN, Critical roles for IFN-beta in
lymphoid development, myelopoiesis, and tumor development: links to tumor necrosis factor alpha. Proceedings of
the National Academy of Sciences of the United States of
America, 100(23):13453-8, 2003.
82. DePaolo RW, Rollins BJ, Kuziel W and Karpus WJ,
CC chemokine ligand two and its receptor regulate mucosal
production of IL-12 and TGF-B in high dose oral tolerance.
Journal of Immunlogy, 171: 3560-3567, 2003.
83. Dezso Z, Oltvai ZN and Barabasi AL, Bioinformatics
analysis of experimentally determined protein complexes in
the yeast saccharomyces cerevisiae. Genome Research, Vol 13,
pp 2450-2454, 2003.
84. Ding R, Logemann JA, Larson CR and
Rademaker AW, The effects of taste and consistency on
swallow physiology in younger and older healthy individuals:
a surface electromyographic study. Journal of Speech,
Language, & Hearing Research, 46(4):977-89, 2003.
85. Drane DL and Logemann J, An explanation for
the association between specific language impairment and
toxemia. Medical Hypotheses, 61(2):223-8, 2003.
86. Drincic A, Arseven OK, Sosa E, Mercado M, Kopp P
and Molitch ME, Men with acquired hypogonadotropic
hypogonadism treated with testosterone may be fertile.
Pituitary, Vol 6, pp 5-10, 2003.
87. Duan L, Miura Y, Dimri M, Majumder B, Dodge IL,
Reddi AL, Ghosh A, Fernandes N, Zhou P, MullaneRobinson K, Rao N, Donoghue S, Rogers RA, Bowtell D,
Naramura M, Gu H, Band V and Band H, Cbl-mediated
ubiquitinylation is required for lysosomal sorting of epidermal
growth factor receptor but is dispensable for endocytosis.
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88. Dumanian GA, Ondra SL, Liu J, Schafer MF and
Chao JD, Muscle flap salvage of spine wounds with souft tissue
defects or infection. Spine, Vol 28 (11), 1203-1211, 2003.
89. Durie BG, Kyle RA, Belch A, Bensinger W, Blade J,
Boccadoro M, Child JA, Comenzo R, Djulbegovic B, Fantl
D, Gahrton G, Harousseau JL, Hungria V, Joshua D, Ludwig
H, Mehta J, Singhal S, et al, Myeloma management guidelines: a consensus report from the Scientific Advisors of the
International Myeloma Foundation. Hematolgy Journal
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90. Dwir O, Solomon A, Mangan S, Kansas GS,
Schwarz US and Alon R, Avidity enhancement of L-selectin
bonds by flow: shear-promoted rotation of leukocytes turn
labile bonds into functional tethers. Journal of Cell Biology,
163(3):649-59, 2003.
91. Engleman MA and Small W, Combined modality
therapy in the treatment of gynecologic malignancies.
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92. Escobar PF, Lurain JR, Singh DK, Bozorgi K and
Fishman DA, Treatment of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D,
cyclophosphamide, and vincristine chemotherapy. Gynecologic
Oncology, 91(3):552-7, 2003.
93. Fazleabas AT, Brudney A, Chai D, Langoi D and
Bulun SE, Steroid receptor and aromatase expression in
baboon endometriotic lesions. Fertility & Sterility, 80 Suppl
2:820-7, 2003.
94. Fehrmann F and Laimins LA, Human papillomaviruses: targeting differentiating epithelial cells for
malignant transformation. Oncogene, 22(33):5201-7, 2003.
95. Ferris FD, von Gunten CF and Emanuel LL,
Competency in end-of-life care: last hours of life. Journal
of Palliative Medicine, 6(4):605-13, 2003.
96. Fitzgibbon ML, Sanchez-Johnsen LA and
Martinovich Z, A test of the continuity perspective across
bulimic and binge eating pathology. International Journal
of Eating Disorders, 34(1):83-97, 2003.
97. Focia PJ, Alam H, Lu T, Ramirez UD and
Freymann DM, Novel protein and Mg2+ configurations in
the Mg2+GDP complex of the SRP GTPase ffth. Proteins,
Vol 54, pp 222-230, 2003.
98. Folsch H, Pypaert M, Maday S, Pelletier L and
Mellman I, The AP-1A and AP-1B clathrin adaptor complexes
define biochemically and functionally distinct membrane domains.
Journ of Cell Biology, Vol 163, No 2, pp 351-362, 2003.
59
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99. Frankel AE, Fleming DR, Hall PD, Powell BL,
Black JH, Leftwich C and Gartenhaus R, A phase II study
of DT fusion protein denileukin diftitox in patients with
fludarabine-refractory chronic lymphocytic leukemia.
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100. Fraser TG, Smith ND and Noskin GA, Persistent
methicillin-resistant Staphylococcus aureus bacteremia due
to a prostatic abscess. Scandinavian Journal of Infectious
Diseases, 35(4):273-4, 2003.
101. Frater JL, Yaseen NR, Peterson LC, Tallman MS
and Goolsby CL, Biphenotypic acute leukemia with coexpression of CD79a and markers of myeloid lineage. Arch Pathol
Lab Med, Vol 127, pp 356-359, 2003.
102. Gann PH, Informed consent for prostate-specific
antigen testing. Urology, Vol 61, pp 5-6, 2003.
103. Gann PH, Combining biomarkers to detect disease
with application to prostate cancer. Biostatistics, Vol 4, No 4,
pp 523-538, 2003.
104. Gann PH, Chatterton RT, Gapstur SM, Liu K,
Garside D, Giovanazzi S, Thedford K and Van Horn L,
The effects of a low-fat/high-fiber diet on sex hormone levels
and menstrual cycling in premenopausal women: a 12-month
randomized trial (The Diet and Hormone Study), 93rd
Annual Mtg of Am Assn for Cancer Res (4/6-10/02).
Am Cancer Soc, 2003.
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Experimental Medicine, 198(10):1551-62, 2003.
320. Vogel TU, Reynolds MR, Fuller DH, Vielhuber K,
Shipley T, Fuller JT, Kunstman KJ, Sutter G, Marthas ML,
Erfle V, Wolinsky SM, Wang C, Allison DB, Rud EW,
Wilson N, Montefiori D, Altman JD, Watkins DI,
Multispecific vaccine-induced mucosal cytotoxic T lymphocytes reduce acute-phase viral replication but fail in long-term
control of simian immunodeficiency virus SIVmac239. Journal
of Virology, 77(24):13348-60, 2003.
321. Von Roenn JH, Clinical presentations and standard
therapy of AIDS-associated Kaposi’s sarcoma. Hematology Oncology Clinics of North America, 17(3):747-62, 2003.
322. Vorobjev IA, Alieva IB, Grigoriev IS, Borisy GG,
Microtubule dynamics in living cells: direct analysis in the
internal cytoplasm. Cell Biology International, 27(3):
293-4, 2003.
323. Vreeland WN, Williams SJ, Barron AE, Sassi AP,
Tandem isotachophoresis-zone electrophoresis via basemediated destacking for increased detection sensitivity
in microfluidic systems. Analytical Chemistry, 75(13):
3059-65, 2003.
324. Wang EY, Ma EY and Woodruff TK, Activin signal
transduction in the fetal rat adrenal gland and in human
H295R cells. J Endocrinol, 178(1): 137-148, 2003.
325. Wang K, Weinrach D, Lal A, Musunuri S, Ramirez J,
Ozer O, Keh P, Rao MS, Signet-ring cell change versus
signet-ring cell carcinoma: a comparative analysis. American
Journal of Surgical Pathology, 27(11):1429-33, 2003.
326. Wang XQ, Sun P, Paller AS, Ganglioside GM3
Blocks the Activation of Epidermal Growth Factor Receptor
Induced by Integrin at Specific Tyrosine Sites. J Biol Chem,
Vol 278, No 49, pp 48770-48778, 2003.
327. Wang Y, Yang X, Liu H, Tang X, Study on effects
of Erigeron breviscapus extract on anticoagulation. [Chinese]
Zhong Yao Cai, 26(9):656-8, 2003.
328. Weinfurt KP, Castel LD, Li Y, Sulmasy DP,
Balshem AM, Benson AB 3rd, Burnett CB, Gaskin DJ,
Marshall JL, Slater EF, Schulman KA, Meropol NJ,
The correlation between patient characteristics and
expectations of benefit from Phase I clinical trials.
Cancer, 98(1):166-75, 2003.
329. Weinstein JL, Katzenstein HM and Cohn SL,
Advances in the diagnosis and treatment of neuroblastoma.
Oncologist, 8(3):278-92, 2003.
330. Weiss J, Meeks JJ, Hurley L, Raverot G, Frassetto A,
Jameson JL, Sox3 is required for gonadal function, but not
sex determination, in males and females. Molecular & Cellular
Biology, 23(22):8084-91, 2003.
331. Winchester DJ, Bernstein JR, Jeske JM,
Nicholson MH, Hahn EA, Goldschmidt RA, Watkin WG,
Sener SF, Bilimoria MB, Barrera, Jr, E, Winchester DP,
Upstaging of Atypical Ductal Hyperplasia After VacuumAssisted 11-Gauge Stereotactic Core Needle Biopsy. Arch
Surg 138:619-623, 2003.
332. Wisco D, Anderson ED, Chang MC, Norden C,
Boiko T, Folsch H, Winckler B, Uncovering multiple axonal
targeting pathways in hippocampal neurons. Journ of Cell
Biology, Vol 162, No 7, pp 1317-1328, 2003.
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Genome-wide scan of brothers: replication and fine mapping
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334. Wood JR, Nelson VL, Ho C, Jansen E, Wang CY,
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The Robert H. Lurie Comprehensive Cancer
Center of Northwestern University
Advisory Boards
Internal Advisory Board
Board Chairman
Jonathan Leis, PhD
Executive Associate Dean
for Research
Feinberg School of Medicine,
Northwestern University
Board Members
Hamid Band, MD, PhD
Professor of Medicine
Director, Division of
Molecular Oncology
Evanston Northwestern
Healthcare
Richard H. Bell Jr., MD
Loyal and Edith Davis
Professor and Chairman,
Department of Surgery
Al B. Benson III, MD
Associate Director,
Clinical Investigations
Robert H. Lurie
Comprehensive Cancer Center
of Northwestern University
Raymond Curry, MD
for Education
Leo I. Gordon, MD
Professor and Chief, Division
of Hematology/Oncology,
Department of Medicine
Associate Director,
Clinical Sciences
Robert H. Lurie
70
Philip Greenland, MD
Harry W. Dingman Professor
and Chairman, Department
of Preventive Medicine
Associate Director, Cancer
Prevention and Control
Robert H. Lurie
Mary J.C. Hendrix, PhD
Professor of Pediatrics
President and Director
Children’s Memorial Institute
for Education and Research
J. Larry Jameson, MD, PhD
Irving S. Cutter Professor
and Chairman, Department
of Medicine
Janaradan Khandekar, MD
Louise W. Coon Chairman,
Department of Medicine
Evanston Northwestern
Healthcare
Morris Kletzel, MD
Professor of Pediatrics
Chief, Division of
Hematology/Oncology,
Department of Pediatrics
Children’s Memorial
Medical Center
Timothy M. Kuzel, MD
Associate Professor of Medicine
Associate Director, Clinical
Cancer Center
Robert H. Lurie
Steven T. Rosen, MD
Genevieve Teuton Professor
of Medicine
Director
Robert H. Lurie
Lewis Landsberg, MD
Dean and Vice President
for Medical Affairs
Mary Kathleen Rundell, PhD
Professor of MicrobiologyImmunology
Associate Director, Education
Robert H. Lurie
Jeffrey C. Miller
Senior Executive Associate
Dean, Chief Operating Officer
C. Bradley Moore, PhD
Vice President for Research
Leonidas C. Platanias,
MD, PhD
Jesse, Sara, Andrew, Abigail,
Benjamin, and Elizabeth Lurie
Professor of Cancer Research
Deputy Director
Robert H. Lurie
Janardan K. Reddy, MD
Magerstadt Professor and
Chairman, Department
of Pathology
Robert Rosa, MD
for Clinical Affairs
James Schroeder, MD
President and CEO
Northwestern Medical
Faculty Foundation
Timothy Volpe
Associate Director,
Administration
Robert H. Lurie
Teresa K. Woodruff, PhD
Associate Professor of
Neurobiology and Physiology
Associate Director,
Basic Sciences
Robert H. Lurie
James Young, MD
Executive Associate Dean,
Faculty Affairs
85898 NUMS Journal
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External Advisory Board
Stephen B. Baylin, M.D.
Professor of Oncology
and Medicine
Sidney Kimmel
at Johns Hopkins
Baltimore, MD
David DeMets, Ph.D.
Chairman, Department
of Biostatistics
University of Wisconsin
Medical School
Madison, WI
Page 71
Robert B. Diasio, M.D.
Chairman, Department of
Pharmacology and Toxicology
University of Alabama,
Birmingham
Birmingham, AL
Richard Payne, M.D.
Chief, Pain and Palliative
Care Service
Memorial Sloan-Kettering
Cancer Center
New York, NY
Margaret A. Tempero, M.D.
Deputy Director, UCSF
University of California,
San Francisco
San Francisco, CA
Paul F. Engstrom, M.D.
Senior Vice President for
Population Science
Fox Chase Cancer Center
Philadelphia, PA
Phyllis M. Rideout, Ph.D.
Assoc. Director for
Administration and Education
USC/Norris Comprehensive
Cancer Center
University of Southern
California
Los Angeles, CA
Max Wicha, M.D.
Director, University of
Michigan Comprehensive
Cancer Center
Ann Arbor, MI
71
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Page 72
Members who contributed to this issue
Articles:
Abstracts:
Ashok Aiyar, PhD
Assistant Professor
of Microbiology
and Immunology
(312) 503-3167
Raymond Bergan, MD
Associate Professor
of Medicine
(312) 908-5284
Vadim Backman, PhD
Assistant Professor of
Biomedical Engineering
(847) 491-3536
Gary Borisy, PhD
Leslie B. Arey Professor of
Cell and Molecular Biology
(312) 503-2852
Deborah Dobrez, PhD
Research Scientist and
Research Assistant Professor
(312) 503-1543
Peter Gann, MD, ScD
Preventive Medicine
(312) 908-8432
Hemant K. Roy, MD
Internal Medicine
(847) 657-1900
Lonnie Shea, PhD
Chemical and Biological
Engineering
(847) 491-7398
William Small, Jr., MD
Radiology
(312) 926-3521
Ramesh Wali, PhD
Research Associate Professor
of Medicine
(847) 570-7684
72
Gary Borisy, PhD
Leslie B. Arey Professor of
Biomedical Engineering
(312) 503-2852
David Cella, PhD
Research Professor of
Center on Outcomes
Research and Education
(847) 570-1730
Robert T. Chatterton,
Jr, PhD
Professor of Obstetrics
and Gynecology
(312) 908-1569
Susan L. Cohn, MD
Associate Professor
of Pediatrics
(312) 908-9404
Vincent L. Cryns, MD
Assistant Professor of Medicine
(312) 503-0644
Elizabeth A. Hahn, MA
Research Assistant Professor of
Center on Outcomes Research
and Education
(847) 570-1728
Ishwar Radhakrishnan, PhD
Biochemistry, Molecular
Biology and Cellular Biology
(847) 467-1173
Linda Hicke, PhD
Assistant Professor of BMBCB
(847) 467-4490
Mary Kathleen Rundell,
PhD
Professor of MicrobiologyImmunology
(312) 503-5917
Jonathan Jones, PhD
Professor of Cell and
Molecular Biology
(312) 503-1412
Seema A. Khan, MD
Associate Professor of Surgery
(312) 695-4845
James M. Kozlowski, MD
Associate Professor of Urology
(312) 908-4974
Alfonso Mondragón, PhD
Professor of Biochemistry,
Molecular Biology and
Cell Biology
(847) 491-7726
Monica Morrow, MD
Professor of Surgery
(312) 908-9039
Deborah Dobrez, PhD
Research Scientist and
Research Assistant Professor
(312) 503-1543
LoAnn C. Peterson, MD
Professor of Pathology
(312) 908-2687
Peter Gann, MD, ScD
Preventive Medicine
(312) 908-8432
Michael R. Pins, MD
Assistant Professor
of Pathology
(312) 908-3211
Charles L. Goolsby, PhD
Associate Professor
of Pathology
(312) 908-2430
Leonidas C. Platanias,
MD, PhD
(312) 908-5250
Kathleen Green, PhD
Professor of Pathology
(312) 503-5300
Alfred Rademaker, PhD
Professor of Preventive
Medicine
(312) 908-1970
Stephen F. Sener, MD
Professor of Surgery
(847) 570-1328
Paula H. Stern, PhD
Professor of Molecular
Pharmacology and
Biological Chemistry
(312) 503-8290
Martin S. Tallman, MD
Associate Professor
of Medicine
(312) 908-9412
Zhou Wang, PhD
Assistant Professor of Urology
(312) 908-2264
David J. Winchester, MD
Assistant Professor of Surgery
(847) 570-2800
David P. Winchester, MD
Professor of Clinical Surgery
(847) 570-2800
Teresa Woodruff, PhD
Neurobiology and Physiology
(847) 491-2666
Nabeel R. Yassen, MD, PhD
Assistant Professor
of Pathology
(312) 503-2093
85898 NUMS Journal
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Page 73
The Journal of the
Index to Volume IX,
Number 1
Chuhan Chung, Veronica
M. Stellmach and Susan
E. Crawford
Pigment Epithelium-Derived
Factor (PEDF): An Emerging
Anti-Angiogenic Agent
Morris Kletzel and
Reggie Duerst
Ten Years of Hematopoietic
Stem Cell Transplantation at
Children’s Memorial Hospital
Rumi S. Bhattacharyya
and Paula H. Stern
Role of Insulin-Like Growth
Factor I and the MAP Kinase
Pathway in the Anabolic
Effects of LNCaP Prostate
Cancer Cells on Skeletal Tissue
Robert T. Elder and
Yuqi Zhao
Effect of HIV-1 Viral Protein
R on Cell Cycle G2/M
Controls and Its Potential
Implication in Anticancer
Therapy
Victor V. Levenson and
Ronald B. Gartenhaus
DNA Methylation Biomarkers
for Cancer Diagnosis and
Prognosis
Selected Abstracts of
Publications by Robert
H. Lurie Comprehensive
Cancer Center Members
January 2002 to March 2003
Selected Bibliography of
Publications by Robert
H. Lurie Comprehensive
Cancer Center Members
January 2002 to March 2003
Notable Robert H. Lurie
Comprehensive Cancer
Center Member
Monica Morrow, MD
73
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Page 74
Cancer Center Events
CONTINUING MEDICAL EDUCATION PROGRAMS
Throughout the year, the Robert H. Lurie Comprehensive Cancer Center of Northwestern
University offers Continuing Medical Education (CME) programs on various cancer specialties.
Below is a list of the programs for the remainder 2004. For specific dates or more information about
these programs, visit www.cancer.northwestern.edu or call the Cancer Center at (312) 695-1304.
NCCN Regional Guidelines Symposium: Colon, Rectal, Anal and Pancreatic Cancers
June 25, 2004
American Society of Clinical Oncology 2004 Review
July 30, 2004
Chair: William Gradishar, MD
7th Annual Oncology Nursing Conference
October 8, 2004
6th Annual Lynn Sage Breast Cancer Symposium
Oct. 28-31, 2004
Chairs: William Gradishar, MD,
V. Craig Jordan, OBE, PhD, DSc, Monica Morrow, MD
COMMUNITY EVENTS/PATIENT PROGRAMS
The Cancer Center is committed to educating the public about cancer prevention and treatment.
Many community events and patient programs are offered throughout the year. For more information about these programs, please visit www.cancer.northwestern.edu or call the Cancer Center
Special Events Hotline at (312) 695-1304.
Cancer Survivors’ Celebration and Walk
June 6, 2004 (National Cancer Survivor’s Day)
Lynn Sage Breast Town Hall Meeting
September 12, 2004
74
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Page 75
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
C H I C A G O
Affiliated Research Facilities and Teaching Hospitals
NORTHWESTERN
MEMORIAL HOSPITAL
REHABILITATION INSTITUTE
OF CHICAGO
VA CHICAGO
HEALTHCARE SYSTEM
FEINBERG SCHOOL
OF MEDICINE
NORTHWESTERN UNIVERSITY
DOMINICK DIMATTEO
CANCER RESEARCH LABORATORIES
ROBERT H. LURIE
MEDICAL RESEARCH CENTER
C H I L D R E N ’ S
T
he Robert H. Lurie Comprehensive
Cancer Center of Northwestern
University is the focus of cancer research,
treatment and education at Northwestern
University. The Cancer Center coordinates and integrates the University’s
cancer and cancer-related activities and
unites scientists, clinicians and educators
in the fight against cancer. The Cancer
CHILDREN’S MEMORIAL
HOSPITAL
CHILDREN’S MEMORIAL
INSTITUTE FOR EDUCATION
AND RESEARCH
Center’s administrative offices and many
of its basic science research activities are
at Northwestern University’s Feinberg
School of Medicine on the Chicago
campus. Additional offices and basic
science research labs are located on the
Evanston campus. Clinical research is
E V A N S T O N
conducted at the Feinberg School of
Medicine’s various affiliated teaching
hospitals: Northwestern Memorial
Hospital, Children’s Memorial Hospital,
Evanston Northwestern Healthcare, the
Rehabilitation Institute of Chicago and
EVANSTON NORTHWESTERN
HEALTHCARE
ARTHUR AND GLADYS PANCOE
EVANSTON NORTHWESTERN
HEALTHCARE LIFE SCIENCES PAVILION
Veterans Administration Chicago
Healthcare System.
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85898 NUMS Journal - Robert H. Lurie Comprehensive Cancer

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