2014-2015

Transcription

2014-2015

Aichi Cancer Center
Research Institute
Scientific Report
2014 – 2015
Chikusa-ku, Nagoya 464-8681
Japan
(The Cover)
The Aichi Cancer Center Research Institute Main Building,
photo courtesy of Dr. Keitaro Matsuo
Published by
Dr. Taira Kinoshita
President
Aichi Cancer Center Research Institute
1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
Telephone: 052-762-6111
Facsimile: 052-763-5233
Editorial Committee
Dr. Masahiro Aoki (Division of Molecular Pathology)
Dr. Keiichiro Sakuma (Division of Molecular Pathology)
Dr. Malcolm A. Moore, English Editor
Printed by
Nagoya University COOP
1 Furoucho, Chikusa-ku, Nagoya 464-0814, Japan
Contents
Preface
Taira Kinoshita
1
Organization of the Aichi Cancer Center Research Institute
2
Scientific Reports
Division of Epidemiology and Prevention
General Summary
1. Descriptive epidemiology
1.1. Advances and set-backs/persisting problems in the treatment of lymphoma
and myeloma patients: Analysis of survival using population-based cancer
registry data in Japan from 1993 to 2006
Chihara, D., Ito, H., Izutsu, K., Hattori, M., Nishino, Y., Ioka, A., Matsuda, T.,
and Ito, Y.
1.2. Declining trends in prevalence of Helicobacter pylori infection by birth-year
in a Japanese population
Watanabe, M., Ito, H., Hosono, S., Oze, I., Ashida, C., Tajima, K., Katoh, H.,
Matsuo, K., and Tanaka, H.
2. The hospital-based epidemiologic research program at Aichi Cancer Center
(HERPACC) study
2.1. Impact of metallothionein gene polymorphisms on the risk of lung cancer
Ito, H., Nakane, H., Hirano, M., Hosono, S., Oze, I., Matsuda, F., Tanaka, H.,
Matsuo, K.
2.2. Polymorphisms in CYP19A1, HSD17B1 and HSD17B2 genes and serum
sex hormone levels among postmenopausal Japanese women
Hosono, S., Ito, H., Oze, I., Higaki, Y., Morita, E., Takashima, N., Suzuki, S.,
Shimatani, K., Mikami, H., Ohnaka, K., Ozaki, E., Katsuura-Kamano, S.,
Kubo, M., Nagata, C., Naito, M., Hamajima, N., Tanaka, H., and
for the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study Group.
2.3. Comparison of circulating miRNA levels between gastric cancer patients
and non-cancer controls
Oze, I., Nagasaki, H., Shimada, S., Akiyama, Y., Hosono, S., Ito, H.,
Watanabe, M.,Yatabe, Y., Tanaka, H., Matsuo, K., Yuasa, Y.
3. Tobacco control
3.1. Factors associated with successful and maintained quit smoking status among
patients who received Japanese smoking cessation therapy
Tanaka, H., Taniguchi, C., Saka, H., Oze, I., Tachibana, K., Nozaki, Y.,
Suzuki, Y., Suehisa, H., Sakakibara, H.
Division of Oncological Pathology
General Summary
1. Coxsackie and adenovirus receptor – a
novel negative regulator of RhoA
associated kinase (ROCK) - is a critical regulator of survival and growth of oral
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9
11
i
squamous carcinoma cells
Saito, K., Sakaguchi, M., Iioka, H., Matsui, M., Nakanishi, H., Huh N.,
and Kondo, E.
2. A extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor
growth of human malignant melanoma cells
Ruma IMW, Putranto EW, Kondo E, Watanabe R, Saito K, Inoue Y,
Yamamoto K, Nakata S, Kaihata M, Murata H and Sakaguchi M
3. Development of a New Rapid Isolation Device for Circulating Tumor Cells
(CTCs) using 3D Palladium Filter and its Application for Genetic Analysis
Yusa A, Toneri T, Masuda T, Ito S, Yamamoto S, Okochi M, Kondo N, Iwata H,
Yatabe Y, Ichinosawa Y, Kinuta S, Kondo E, Honda H, Arai F, Nakanishi H.
4. New whole-body multimodality imaging of gastric cancer peritoneal metastases
combining fluorescence imaging with ICG-labeled antibodies and MRI in mice
Ito A, Ito Y, Matsushima S, Tsuchida D, Ogasawara M, Hasegawa J, Misawa K,
Kondo E, Kaneda N, Nakanishi H.
Division of Molecular Oncology
General Summary
1. Functional differences between wild-type and mutant-type BAP1 tumor
suppressor against malignant mesothelioma cells
Hakiri, S., Osada, H., Ishiguro, F., Murakami, H., Murakami-Tonami, Y.,
Yokoi, K., and Sekido, Y.
2. SMC2 regulates the transcription of DDR genes and shows synergistic phenotype
with MYCN
Murakami-Tonami, Y., Kishida, S., Takeuchi, I., Katou, Y., Maris, JM.,
Ichikawa, H., Kondo, Y., Sekido, Y., Shirahige, K., Murakami, H., and
Kadomatsu, K.
Division of Molecular Medicine
General Summary
1. Establishing prediction models of upper-aerodigestive tract cancer using
molecular and environmental information
Koyanagi, Y., Ito, H., Oze, I., Hosono, S., Watanabe, M., Tanaka, H., Abe, T.,
Shimizu, Y., Hasegawa, Y., and Matsuo, K.
2. Generation of mouse models of lymphoid neoplasms using retroviral gene
transduction of in vitro-induced germinal center B cells
Takahara T., Arita, K., Yoshida, N., Sugiyama, T., Seto, M., and Tsuzuki, S.
3. Establishment of a new mouse model of adult T cell leukemia
Kasugai-Maeda, Y., Yoshida, N., Seto, M., and Tsuzuki, S.
4. Clonal heterogeneity of lymphoid malignancies correlates with poor prognosis
Katayama, M., Yoshida, N., Umino A., Kato H., Tagawa, H., Nakagawa, M.,
Fukuhara, N., Sivasundaram, S., Takeuchi, I., Hocking TD., Arita, K.,
Karube, K., Tsuzuki. S, Nakamura, S., Kinoshita T., and Seto, M.
5. Establishment of a model of YAP-driven malignant mesothelioma
Kakiuchi, T., Takahara, T., Kasugai-Maeda, Y., Arita, K., Yoshida, N.,
Karube, K., Katayama, M., Nakanishi, H., Kiyono, T., Nakamura, S., Osada, H.,
Sekido, Y., Seto, M., and Tsuzuki, S.
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ii
Division of Immunology
General Summary
1. Identification of a naturally processed HLA-Cw7-binding peptide that
cross-reacts with HLA-A24-restricted ovarian cancer-specific CTLs
Demachi-Okamura, A., Yamada, E., Kondo, S., Shibata, K., Kikkawa, F.,
and Kuzushima, K.
2. Interaction of Vα24 iNKT cells with dendritic cells increases the therapeutic
efficacy of TCR-gene modified T cells
Zhang, R., Uemura, Y., Liu, T., Ikeda, H., Okamoto, S., Tatsumi, M., Mineno, J.,
Shiku, H., and Kuzushima, K.
3. Cellular adjuvant properties and direct cytotoxicity in rejuvenated Vα24 invariant
NKT cells from human induced pluripotent stem cells
Zhang, R., Kitayama, S., Liu, R., Ueda, N., Tatsumi, M., Kaneko, S.,
Kuzushima, K., and Uemura, Y.
4. Depletion of DSS1, which is a member of mammalian TREX2 complex and
maintains BRCA2 stability, confers breast cancer cells highly-sensitive to
anti-cancer drugs through DNA damage
Gondo, N., Rezano A., Ohta, R., Kuzushima, K., Toyama, T., and Kuwahara, K.
Division of Microbiology and Oncology
General Summary
1. Spatial regulation of Src via lipid rafts controls cancer progression
Oneyama, C., Kuwahara, A., Miyata, M., and Watanabe, R.
2. MicroRNA-mediated gene expression controls Src-related oncogenic signaling
Oneyama, C., Ninomiya, Y., Miyata, M., and Watanabe, R.
3. Clustered microRNAs of the Epstein- Barr virus cooperatively downregulate
an epithelial cell-specific metastasis suppressor
Kanda, T., and Miyata, M.
4. A herpesvirus specific motif of Epstein-Barr virus DNA polymerase is required
for efficient lytic genome synthesis
Narita, Y., Kawashima, D., Kanda, T., Tsurumi, T., and Murata, T.
Division of Molecular Pathology
General Summary
1. An in vivo shRNA screen identifies HNRNPLL as a novel colorectal cancer
metastasis suppressor
Sakuma, K., Sasaki, E., Kimura, K., Komori, K., Shimizu, Y., Yatabe, Y.,
and Aoki, M.
2. Simultaneous inhibition of mTOR and EGFR suppresses invasion of intestinal
adenocarcinoma in cis-Apc+/Δ716 Smad4+/- mice
Fujishita, T., Kojima, Y., Kajino, R., Taketo, MM., and Aoki, M.
3. The MEK/ERK signaling inhibition suppresses intestinal polyp formation by
reducing the stromal COX-2 and CCL2 levels
Fujishita, T., Kajino, R., Kojima, Y., Taketo, MM., and Aoki, M.
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Division of Biochemistry
iii
General Summary
1. Ndel1 is a suppressor of primary cilia assembly
Inaba, H., Goto, H., Kasahara, K., Inoko, A., He, D., Tanigawa, N., Hayashi, Y.,
Kobori, K., Kumamoto, K., Yonemura, S., Goshima, N., Yamano S.,
Wanibuchi, H., Kiyono, T., Hirotsune, S., and Inagaki, M.
2. The ubiquitin-proteasome system controls primary cilia formation at the initial
step of axoneme extension
Kasahara, K., Aoki H., Kawamoto E., Kawakami Y., Kiyono T., Kawamura Y.,
Goshima N., and Inagaki M.
3. Cytokinetic failure induces aneuploidy and aging in vimentin
Tanaka, Hir., Goto, H., Inoko, A., Hayashi, Y., Kobori, K., Tanigawa, N.,
Makihara, H., Izawa, I., and Inagaki, M.
4. Novel platform for integrating centrosomal functions
Inoko, A., Hayashi, Y., Kiyono, T., Goshima, N., and Inagaki, M.
Central Service Unit
General Summary
1. Relationship between risk of esophageal cancer and the number of
polymorphisms in mitochondrial DNA
Kumimoto, H.
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Librarians
Publications
1. Journals
2. Reviews and books
3. Abstracts for international conferences
Records of Seminars
Records of Symposium
iv
From left to right
Ms. T. Hayashi and Dr. T. Kinoshita
Preface
_______________________________________________________________________________________
It is my pleasure to share with you the 24th Scientific Report (2014-2015) of the Aichi Cancer Center
Research Institute. Since its establishment in 1964, Scientific Reports have been published biennially to
document major research activities and highlight progress in and contributions to cancer research worldwide.
As illustrated on the following pages, the Research Institute consists of 8 Divisions, along with a Central
Service Unit, an Animal Facility and a Laboratory of Translational Research, with overall research emphasis
on
three
areas:
cancer
prevention/epidemiology;
preclinical/experimental
therapy;
and
carcinogenesis/molecular biology. In addition, the institute is affiliated with the Nagoya University Graduate
School of Medicine and the Nagoya City University Graduate School of Pharmaceutical Sciences. At the
present time 7 professors and 4 associated professors nominated from the chiefs and section heads of the
Research Institute are engaged in education of graduate school students at the two universities. In Aichi
Cancer Center Research Institute itself, a total of 62 staff members, 29 researchers and 22 research assistants,
as well as 11 research residents, are now conducting a wide range of studies, together with 7 graduate school
students, and approximately 25 visiting research fellows and 40 temporary research assistants.
The major areas being pursued are as follows:
- descriptive and analytical epidemiology of cancers
- primary and secondary prevention of cancer
- molecular pathogenesis of intractable malignancies
- peptide-based anti-cancer DDS technology
- molecular oncology of malignant mesotheliomas and lung cancers
- identification and characterization of new cancer-associated genes
- molecular biology of translocation-junction genes in hematopoietic tumors
- molecular epidemiology and it's application in clinical practice/prevention
- basic studies for cancer immunotherapy
- genetic approaches to breast cancer susceptibility and prognosis
- molecular basis of oncogene-mediated cancer progression
- human viral oncogenesis
- molecular mechanisms of colorectal cancer metastasis
- pathophysiology of cancer cachexia
- molecular mechanisms of cell proliferation and movement
- ciliary dynamics in carcinogenesis
More detailed descriptions of the individual research topics of each Division appear in the contents of
this report. It is our sincere hope that the activities of the Institute will make a major contribution to
elucidation of the mechanisms of carcinogenesis and to development of novel clinical applications in cancer
diagnosis, treatment and prevention.
Finally, I would like to express my deep appreciation to the Aichi Prefectural Government for the
continuous support received since this Institute was founded in 1964. Granting support from the Ministry of
Education, Science, Sports, Culture and Technology, the Ministry of Health, Labor, and Welfare, and the
Ministry of Economy, Trade and Industry, as well as other related organizations in Japan, is also gratefully
acknowledged.
January, 2016
Taira Kinoshita, M.D., M.P.H., D.M.Sci.
Acting Director, President
1
Organization of the Aichi Cancer Center Research Institute
_______________________________________________________________________________________
2
SCIENTIFIC REPORTS
From left to right
First row: Dr. I. Oze, Dr. S. Hosono, Dr. H. Tanaka, Dr. H. Ito, Ms. M. Watanabe, Dr. H.
Nakagawa
Second row: Ms. N. Kawamura, Ms. A. Yoshida, Ms. S. Nimura, Ms. I. Kato, Ms. R. Niwa,
Dr. S. Inoue, Ms. Y. Mano, Ms. Y. Sugino
Third row: Ms. A. Hiraiwa, Ms. T. Nishiwaki, Ms. M. Miyoshi, Ms. Y. Taniguchi, Ms. K.
Koide, Ms. M. Kawaguchi, Ms. S. Inui, Ms. T. Ito
4
Division
of Epidemiology and Prevention
________________________________________________________________________________
Hideo Tanaka, M.D., PhD. Chief
Hidemi Ito, M.D., PhD., M.P.H. Section Head (as of April 2009)
Satoyo Hosono, M.D., PhD. Senior Researcher (as of April 2009)
Isao Oze, M.D. Senior Researcher (as of April 2012)
Koichi Fukumoto, M.D. Research Resident (Until March 2014)
Dai Chihara, M.D., PhD. Research Resident (Until June 2014)
Hiroko Nakagawa, M.D., PhD. Research Resident (as of April 2014)
Shusaku Inoue, M.D. Research Resident (as of April 2015)
Miki Watanabe, MSc. Research Assistant (as of April 2006)
Tomoko Ito. Research Assistant (as of April 2012)
Yasuo Morishima, M.D. PhD. Researcher (as of April 2011)
Keitaro Matsuo, M.D., PhD., S.M. Researcher (until June 2015)
Visiting Trainees
Daisuke Kawakita, M.D., PhD. Nagoya City University
Hideo Nakane, PhD. Toyota Central R&D Labs., Inc.
Dai Chihara, M.D. Nagoya University Graduate School of Medicine
Akiyo Yoshimura, M.D. Aichi Cancer Center Hospital
Satoko Morishima, M.D, PhD. Fujita Health University School of Medicine
Chie Taniguchi, MSc. Sugiyama Jogakuen University
Michiyo Yamaguchi.
General Summary
The current research activities of the Division of Epidemiology and Prevention cover the following three
subjects: (1) descriptive epidemiology of cancer incidence, mortality and survival using data from the Aichi
Prefectural Cancer Registry and other population-based registries in a collaborative study; (2) analytical
epidemiology based on the hospital-based epidemiologic research program at Aichi Cancer Center
(HERPACC) to determine risk and protective factors for cancer, with a particular focus on
gene-environmental interactions; and (3) epidemiologic studies for tobacco control.
Our main results in 2014 and 2015 were that: 1) in a review of cancer-registry data of patients with
lymphoma and myeloma in Japan from 1993 to 2006, we observed that relative survival had improved for
cases of Hodgkin lymphoma, diffuse large B-cell lymphoma and follicular lymphoma. In contrast, there was
no significant improvement in survival with peripheral T-cell lymphoma, adult T-cell leukemia/lymphoma or
multiple myeloma; 2) a dramatic decline in the prevalence of H. pylori infection was observed in those born
between 1949 and 1961 in the Japanese population, which should contribute to projected future trend of
decreasing gastric cancer incidence in Japan; 3) polymorphisms in the metallothionein gene were found to be
moderately associated with risk of lung cancer and that the association was modified by lifestyle factors; 4)
CYP19A1 and HSD17B2 polymorphisms might be associated with circulating sex hormone levels in
Japanese postmenopausal women, independent of current BMI; 5) plasma miR-103, miR-107 and miR-194
levels are not useful biomarkers for detecting diffuse-type gastric cancer; 6) having a higher self-efficacy of
quitting smoking and varenicline use are associated with success of Japanese smoking cessation therapy
(SCT), while a strong desire to smoke is a risk factor for obstructing maintained cessation during 12 months
after the end of SCT.
5
1.
and Information Services, National Cancer Center
Descriptive epidemiology
1.2. Declining trends in prevalence of
Helicobacter pylori infection by birth-year
1.1. Advances and set-backs/persisting
problems in the treatment of lymphoma and
myeloma patients: Analysis of survival
using population-based cancer registry
data in Japan from 1993 to 2006
Watanabe, M., Ito, H., Hosono, S., Oze, I., Ashida, C.*1,
Tajima, K.*2, Katoh, H.*1, Matsuo, K.*3, and Tanaka, H.
The age-standardized incidence and mortality rates
for gastric cancer have been decreasing in Japan.
This is likely to be due to some extent to a decrease
in prevalence of Helicobacter pylori (H. pylori)
infection, a major risk factor for neoplasia in the
stomach. Our aim was to characterize the trends in
prevalence of H. pylori infection focusing on
birth-year in a Japanese population. We conducted a
cross-sectional study that included 4,285 subjects
who were born from 1926 to 1989. We defined H.
pylori infection by serum H. pylori antibody titer.
Individuals having H. pylori infection and those
with negative H. pylori antibody titer but positive
pepsinogen test were defined as high-risk
individuals for gastric cancer. We estimated the
birth-year percent change (BPC) of the prevalence
by Joinpoint regression analysis. The prevalence of
H. pylori infection among the subjects born from
1927 to 1949 decreased from 54.0% to 42.0% with
a BPC of -1.2% (95%CI: -1.6% to -0.8%). This was
followed by a rapid decline in those born between
1949 (42.0%) and 1961 (24.0%) with a BPC of
-4.5% (95%CI: -6.0% to -3.0%), and a slower
decline in those born between 1961 (24.0%) and
1988 (14.0%) with a BPC of -2.1% (95%CI: -3.3%
to -0.8%). The proportion of high-risk individuals
for gastric cancer among the subjects born from
1927 to 1942 decreased from 62.0% to 55.0% with
a BPC of -0.8% (95%CI: -1.4% to -0.1%). A
subsequent rapid declining trend was observed in
those born between 1942 (55.0%) and 1972
(18.0%) with a BPC of -3.6% (-3.9% to -3.2%), and
then it became stable. Thus a dramatic decline in
the prevalence of H. pylori infection was observed
in those born between 1949 and 1961. As the
population attributable fraction (PAF) for H. pylori
infection with gastric cancer is considerably large,
this declining trend in prevalence of H. pylori
infection would contribute to a projected future
reduction in gastric cancer incidence in Japan.
Chihara, D.*1, Ito, H.*2, Izutsu, K.*3, Hattori, M.*4,
Nishino, Y.*5, Ioka, A.*6, Matsuda, T.*7, and Ito, Y.*6
There have been significant advances in the
treatment of patients with lymphoma and myeloma.
Although improvements in survival outcome have
been addressed by clinical trials, such studies may
not adequately take into account changes in survival
in the general patient population over time.
Therefore, we reviewed the cancer-registry data of
patients with lymphoma and myeloma in Japan
from 1993 to 2006 and estimated relative survival
(adjusted for competing causes of death in
same-age members of the general population)
according to three periods of diagnosis (1993-1997,
1998-2002 and 2003-2006). We also estimated
conditional 5-year relative survival (5-year survival
rate of patients who have survived 5 years). A total
of 26,141 patients were reviewed and analyzed.
Relative survival improved for Hodgkin lymphoma
(HL, N = 853, +20% improvement), diffuse large
B-cell lymphoma (DLBCL, N = 4,919, +14%
improvement) and follicular lymphoma (FL,
N = 1,333, +13% improvement). In contrast, we
found no significant improvement in survival since
1993 with peripheral T-cell lymphoma (PTCL,
N = 667, +4% improvement), adult T-cell
leukemia/lymphoma (ATLL, N = 2,166, -5%
improvement) or multiple myeloma (MM,
N = 4,914, -2% improvement). Conditional 5-year
survival of HL, DLBCL, FL, PTCL, ATLL and MM
was 88, 87, 79, 63, 53 and 45%, respectively.
Relative survival of patients with HL, DLBCL and
FL significantly improved from 1993 to 2006 in
Japan; in contrast, no improvement was seen with
other related diseases, suggesting unmet needs for
novel treatment strategies.
*1
Department of Lymphoma and Myeloma, MD
Anderson Cancer Center
*2
Department of Epidemiology, Nagoya University
Graduate School of Medicine
*3
Department of Hematology, Toranomon Hospital
*4
Department of Cancer Therapy Center, Fukui
Prefectural Hospital
*5
Division of Cancer Epidemiology and Prevention,
Miyagi Cancer Center Research Institute
*6
Center for Cancer Control and Statistics, Osaka
Medical Center for Cancer and Cardiovascular Diseases
*7
Division of Surveillance, Center for Cancer Control
*1
FALCO biosystems Ltd. Tokai-chuo Laboratory
Department of Public Health and Occupational
Medicine, Mie University Graduate School of Medicine
*3
Division of Molecular Medicine, Aichi Cancer Center
Research Institute
*2
6
Fig. 1. Trends in the prevalence
of Helicobacter pylori (H. pylori)
infection (a) and proportion of
high-risk individuals for gastric
cancer (b). These trends were
characterized
by
the
three-birth-year moving-average
method
with
Joinpoint
Regression
Analysis.
The
resulting trend segments, as
delimited in time by joinpoints,
were described by birth-year
percent change (BPC).
*4
Center for Genomic Medicine, Kyoto University
Graduate School of Medicine and Faculty of Medical
Sciences.
*5
Department of Preventive Medicine, Kyushu
University Faculty of Medical Sciences.
2.
The
hospital-based
epidemiologic
research program at Aichi Cancer Center
(HERPACC) study
2.1. Impact of metallothionein gene
polymorphisms on the risk of lung cancer
*1
*2
2.2.
Polymorphisms
in
CYP19A1,
HSD17B1 and HSD17B2 genes and serum
sex
hormone
levels
among
postmenopausal Japanese women
*3
Ito, H. , Nakane, H. , Hirano, M. , Hosono, S., Oze, I.,
Matsuda, F.*4, Tanaka, H.*1, Matsuo, K.*5
Metallothioneins (MTs) are cysteine-rich proteins
that act as antioxidants. A case-control study was
conducted to assess the effects of gene
polymorphisms in the MT region on the risk of lung
cancer in Japanese subjects: 769 lung cancer cases
and 939 non-cancer controls were included.
Associations were evaluated using logistic
regression models with adjustment for potential
confounders (age, sex, and lifestyle factors
including smoking, drinking, and green-yellow
vegetable intake). We found five polymorphisms in
the MT-1 gene region that showed statistically
significant associations with lung cancer. Of these
polymorphisms, rs7196890 showed the strongest
association (odds ratio: 1.30, P = 0.004, 95%
confidence interval: 1.09-1.55). The impact of the
polymorphism decreased with increase of smoking,
and virtually no association with lung cancer was
observed among heavy smokers whose pack-year
values were 30 or more (odds ratio: 1.02, P = 0.93,
95% confidence interval: 0.67-1.55). These results
suggest that polymorphisms in the MT gene are
moderately associated with the risk of lung cancer
and that the associations are modified by lifestyle
factors.
Hosono, S., Ito, H., Oze, I., Higaki, Y.*1, Morita, E.*2, 3,
Takashima, N.*4, Suzuki, S.*5, Shimatani, K.*6, Mikami,
H.*7, Ohnaka, K.*8, Ozaki, E.*9, Katsuura-Kamano, S.*10,
Kubo, M.*11, Nagata, C.*12, Naito, M.*2, Hamajima, N.*13,
Tanaka, H., and for the Japan Multi-Institutional
Collaborative Cohort (J-MICC) Study Group.
Extraovarian sex hormone production plays an
important role in estrogen biosynthesis in
postmenopausal women. We examined possible
associations between serum sex hormone level and
polymorphisms in CYP19A1, HSD17B1, and
HSD17B2. We also assessed possible interaction
between these polymorphisms and current
overweight in a cross-sectional study. A total of 785
Japanese naturally postmenopausal women were
randomly
selected
from
the
Japan
Multi-Institutional Collaborative Cohort (J-MICC)
study database. Information on lifestyle factors was
obtained from a self-administered questionnaire.
Serum estrogens and androgens levels were
measured by liquid chromatography–tandem mass
spectrometry. Four tag SNPs (single nucleotide
polymorphisms) of CYP19A1, one missense SNP of
HSD17B1 and three tag SNPs of HSD17B2 were
examined by Invader assay. A trend test was
conducted using linear regression. After adjustment
for multiple comparisons, we found that rs4441215
and rs936306 in CYP19A1 and rs4888202 and
rs2955160 in HSD17B2 were associated with
differences in serum estrone level. Further,
rs4441215 and rs936306 were associated with
*1
Department of Epidemiology, Nagoya University
*2
Social Systems Research Laboratory, Toyota Central
R&D Labs., Inc.
*3
Environmental & Applied Biotechnology Laboratory,
Toyota Central R&D Labs., Inc..
7
Gene
db SNP rs
number
Number
(n=785)
CYP19A1 Rs4441215
CC
CG
GG
d
trend P -value
15.3±0.8 (15.3-15.4)
14.3±0.8 (14.2-14.4)
13.4±0.8 (13.2-13.5)
*
0.003
2.94±0.36 (2.90-2.98)
2.54±0.40 (2.50-2.59)
2.18±0.36 (2.11-2.25)
*
<0.001
13.7±0.8 (13.6-13.8)
14.8±0.9 (14.7-14.9)
15.9±0.8 (15.7-16.0)
*
0.001
2.32±0.38 (2.27-2.36)
2.75±0.38 (2.71-2.79)
3.12±0.37 (3.05-3.18)
*
<0.001
15.6±0.8 (15.5-15.7)
14.5±0.7 (14.5-14.6)
13.5±0.7 (13.4-13.6)
*
0.004
2.67±0.39 (2.62-2.73)
2.65±0.38 (2.61-2.69)
2.63±0.39 (2.56-2.69)
0.863
15.3±0.8 (15.2-15.4)
14.4±0.7 (14.3-14.5)
13.4±0.8 (13.2-13.6)
*
0.008
2.61±0.37 (2.56-2.65)
2.67±0.39 (2.63-2.72)
2.70±0.41 (2.62-2.78)
0.368
0.402
286
367
132
0.478
204
412
169
HSD17B2 Rs2955160
GG
GC
CC
d
trend P -value
Estradiol
[mean±SD
(95%CI)] (pg/ml)
0.371
HSD17B2 Rs4888202
CC
CT
TT
d
trend P -value
a, c
Estrone
[mean±SD
(95%CI)] (pg/ml)
317
353
115
CYP19A1 Rs936306
CC
CT
TT
d
trend P -value
a, b
MAF
0.382
294
382
109
a
Multivariate models adjusted for age, postmenopausal period, current BMI, smoking, alcohol consumption, regular exercise,
history of any hormone therapy and SHBG level.
b
31 subjects were excluded due to outlier (estrone>31.6pg/ml).
c
40 subjects were excluded due to outlier (estradiol>8.3pg/ml).
d
Linear regression model
*
Significant P -value after adjusting multiple comparison by Holm procedure
Abbreviations: MAF, minor allele frequency
Table 1. Multivariate-adjusted means of sex steroid hormone levels
*9
Department of Epidemiology for Community Health
and Medicine, Kyoto Prefectural University of Medicine
*10
Department of Preventive Medicine, Institute of
Health Biosciences, The University of Tokushima
Graduate School
*11
Laboratory for Genotyping Development, Center for
Genomic Medicine, RIKEN,
*12
Department of Epidemiology and Preventive Medicine,
Gifu University Graduate School of Medicine
*13
Department of Healthcare Administration, Nagoya
University Graduate School of Medicine
differences in serum estradiol level. None of these
polymorphisms showed any significant interaction
with current body mass index (BMI). Our findings
suggest
that
CYP19A1
and
HSD17B2
polymorphisms might be associated with circulating
sex hormone levels in Japanese postmenopausal
women, independent of current BMI.
*1
Laboratory of Exercise Physiology, Faculty of Sports
and Health Science
*2
Department of Preventive Medicine, Nagoya
*3
Forestry and Forest Products Research Institute
*4
Department of Health Science, Shiga University of
Medical Science
*5
Department of Public Health, Nagoya City University
Graduate School of Medical Sciences
*6
Department of International Islands and Community
Medicine, Kagoshima University Graduate School of
Medical and Dental Science
*7
Division of Cancer Registry, Prevention and
Epidemiology, Chiba Cancer Center Research Institute
*8
Department of Geriatric Medicine, Kyushu University
2.3.
Comparison of circulating miRNA
levels between gastric cancer patients and
non-cancer controls
Oze, I., Nagasaki, H.*1, Shimada, S.*1, Akiyama, Y.*1,
Hosono, S., Ito, H., Watanabe, M., Yatabe, Y.*2, Tanaka,
H., Matsuo, K.*3, Yuasa, Y.*1
Diffuse-type gastric cancer (DGC) exhibits a poor
prognosis and there are no effective serum
biomarkers for early detection. Shimada et al. have
established an E-cadherin/p53 double conditional
knockout (DCKO) mouse line, which recapitulates
human DGC morphologically and molecularly. We
8
cohabitant with smoker, age at smoking initiation,
motivation to quit smoking, self-efficacy of quitting
smoking, the Center for Epidemiologic Studies
depression scale (CES-D), the Fagerström test for
nicotine dependence (FTND), strength of desire to
quit, previous abstinence, and varenicline use.
Analysis of factors associated with maintained
cessation, which was defined as successful
cessation at 3, 6 and 12 months after the SCT, in the
550 abstainers at the end of SCT was subsequently
performed.
Results: Having higher self-efficacy of quitting
smoking (OR: 1.39, 95%CI: 1.06-1.82) and
varenicline use (OR: 2.48, 95% CI: 1.23-5.03) were
associated with success of the SCT. Strong desire to
smoke (OR: 0.67, 95%CI: 0.52-0.88) was a risk
factor for obstructing maintained cessation during
the 12 months after the end of SCT.
Conclusion: Assessment of self-efficacy and
strength of desire to smoke is important for
Japanese SCT participants.
identified three circulating miRNAs (miR-103,
miR-107, miR-194) as biomarkers of detecting
early DGC using this DCKO mouse model. The
purpose of this study was to evaluate the usefulness
of the circulating miRNAs for the detection of
human DGC. Subjects were first-visit outpatients at
Aichi Cancer Center Hospital. Cases were 50
patients with DGC. Controls were age and sex
matched
non-cancer
outpatients.
Lifestyle
information was collected by self-administered
questionnaire. Total RNA was extracted from the
plasma samples with miRNeasy Serum/Plasma Kit,
and then reverse-transcribed using an miScript II
RT Kit. The levels of miRNAs in plasma samples
were determined using an miScript SYBR Green
Kit. Spiked-in cel-miR-39 was analysed as a
normalisation control.The three miRNA levels were
not correlated with any clinical factors. The area
under the ROC curve (AUC) of miR-103, miR-107,
miR-194 and the combination of three miRNAs
were 0.55, 0.56, 0.51 and 0.62, respectively. The
mean miRNA levels were not different between
cases and controls. Thus plasma miR-103, miR-107
and miR-194 levels do not appear to be useful
biomarkers for detecting DGC.
*1
Department of Nursing, Sugiyama Jogakuen University
Department of Respiratory Medicine, National Hospital
Organization Nagoya Medical Center
*3
Department of Respiratory Medicine, National Hospital
Organization Kinki-Chuo Chest Medical Center
*4
Department of Respiratory Medicine, Japan
Community Healthcare Organization Chukyo Hospital
*5
Department of Respiratory Medicine, Kitasato
University Kitasato Institute Hospital
*6
Department of Chest Surgery, National Hospital
Orgnaization Iwakuni Medical Center
*7
Department of Nursing, Nagoya University Graduate
School of Medicine
*2
*1
Department of Molecular Oncology, Tokyo Medical
and Dental University
*2
Department of Pathology and Molecular Diagnostics,
Aichi Cancer Center Hospital
*3
Division of Molecular Medicine, Aichi Cancer Center
Research Institute
3.
Tobacco control
3.1. Factors associated with successful
and maintained quit smoking status among
patients who received Japanese smoking
cessation therapy
Tanaka, H., Taniguchi, C.*1, Saka, H.*2, Oze, I.,
Tachibana, K.*3, Nozaki, Y.*4, Suzuki, Y.*5, Suehisa, H.*6,
Sakakibara, H.*7
Objectives: Although nine years have passed
since the start of the Japanese smoking cessation
therapy (SCT) program, few studies have
investigated cognitive and psychological factors
associated with the success of quitting smoking.
The aim of this study was to identify factors
associated with the success of quitting smoking in
the SCT and 12 months’ maintained cessation
among abstainers in the SCT.
Methods: In a multi-institutional study at six
smoking cessation clinics, we performed
multivariate logistic regression analysis for 660
participants using the following independent
variables: age, sex, having present illness, cohabiter,
9
From front to back
Left row: Dr. H. Iioka, Ms. Y. Ito, Ms. R. Watanabe
Right row: Mr. T. Sato, Ms. Niwa, Dr. K. Saito, Dr. E. Kondo, Ms. M. Tanaka
10
Division
of Oncological Pathology
________________________________________________________________________________
Eisaku Kondo, M.D., PhD. Chief
Hayao Nakanishi, M.D., PhD., Section Head (until Dec. 2013)
Ken Saito, PhD. Senior Researcher (as of April 2013)
Keiko Shinjo, M.D., Ph.D. Senior Researcher (as of April 2012)
Susumu Nakata, M.D. Ph.D. Senior Researcher (as of April 2011)
Daisuke Yamashita, M.D., Research Resident (as of 2013)
Hideaki Ito, M.D., Research Resident (as of April 2014)
Takuya Saito, M.D., Graduate course student (as of April 2012)
Risayo Watanabe. Research Assistant (as of Feb 2013)
Noriko Saito. Research Assistant
Yumiko Ito. Research Assistant (as of April 2012)
Tomoaki Sato. Research Assistant (as of April 2012)
Visiting Scientist
Hidekazu Iioka. M.D., PhD. Aichi Medical University
Akiko Yusa. Nagoya University Faculty of Engineering
Visiting Trainees
Mizuna Tanaka. Meijoh University Faculty of Pharmacy
Kohki Murakami. Nagoya University Graduate School of Medicine.
Tomomi Furuya. Meijoh University Faculty of Pharmacy
Kayoko Terasawa. Meijoh University Faculty of Pharmacy
General Summary
The aim for our research at the Division of Oncological Pathology is to disclose the pathogenesis of
human malignancies, especially focusing on intractable tumors such as advanced stage cancers of the
gastrointestinal tract, including examples in the oral cavity and other head and neck sites, lung cancers, brain
tumors, aggressive leukemias and so on, through molecular analyses based on data obtained by
morphological and biological examination of cancer tissues and human cancer cells. Our interest is now
concretely focused on finding novel therapeutic targets through basic pathological research and molecular
analysis of progression, metastasis, invasion, and stem cell pathology. As a second important aim, we are
also making efforts to develop advanced antitumor medical technologies for clinical application. In addition
to these molecular pathological research activities, another important responsibility of our division is an
autopsy service, which provides a basis for understanding of neoplasia with implications inmmay areas and
providing motivation for new research activity. Postmortem examinations allow valuable information to be
obtained on the behavior of neoplasms and their response to therapy, helping clarify pathogenesis. Thus, the
present aim of our division is to promote comprehensive pathological research and contribute to current and
near-future tumor medicine.
1. Coxsackie and adenovirus receptor – a
novel
negative
regulator
of
RhoA
associated kinase (ROCK) - is a critical
regulator of survival and growth of oral
squamous carcinoma cells
several different origins has been investigated with
respect to tumor genesis, progression and metastasis.
However, its biological functions in tumor cells
remain controversial. We established a critical role
of CAR in growth regulation of oral squamous cell
carcinomas (SCCs) in vitro and in vivo via specific
interaction with Rho-associated protein kinase
(ROCK). In particular, loss of endogenous CAR
expression by knockdown using a specific siRNA
facilitates growth suppression of SCC cells due to
cell dissociation, followed by apoptosis. The
Saito, K., Sakaguchi, M.*1, Iioka, H., Matsui, M.,
Nakanishi, H., Huh N.*1 and Kondo, E.
The Coxsackie and adenovirus receptor (CAR)
is essential for adenovirus infection of target cells.
Constitutive expression in various cancer and
normal tissues has been reported and recently the
biological role of CAR in human neoplasms of
11
Okayama University
consequent morphological reaction appears
reminiscent of anoikis, rather than the
epithelial-mesenchymal transition (EMT), and the
dissociation of oral SCC cells appears to be
triggered not by lack of contact with extracellular
matrix (ECM), but by loss of cell-to-cell contact
caused by abnormal translocation of E-cadherin
from
surface
membranes
to
cytoplasm.
Immunoprecipitation assays of the CAR-transfected
oral SCC cell line, HSC-2, with or without ROCK
inhibitor (Y-27632), revealed that CAR directly
associates with ROCKI and ROCKII, resulting in
inhibition of ROCK activity and contributing to
maintenance of cell-to-cell adhesion for growth and
survival. Based on these findings, in vivo behavior
of CAR-downregulated HSC-2 cells from siRNA
knockdown was compared with that of normally
CAR-expressing
cells
in
intraperitoneally
xenografted mouse models. We found that mice
engrafted with CAR siRNA-pretreated HSC-2 cells
showed poor formation of metastatic foci in
contrast to those implanted with control
siRNA-pretreated cells that maintained endogenous
CAR expression and that disseminated extensive
peritoneal lesions. Thus, CAR substantially impacts
on growth and survival of oral SCC cells through
specific interactions with ROCK in vitro and in
vivo, providing clues for the molecular therapy or
head and neck SCCs.
2. A extract of Cordyceps militaris inhibits
angiogenesis and suppresses tumor
growth of human malignant melanoma cells
Ruma IMW*1, Putranto EW*1, Kondo E, Watanabe R,
Saito K, Inoue Y, Yamamoto K, Nakata S, Kaihata M,
Murata H and Sakaguchi M*1.
Angiogenesis
is
essential
for
tumor
development and metastasis. Among several
angiogenic factors, vascular endothelial growth
factor receptor (VEGF) is important for tumor
angiogenesis and is commonly overexpressed in
solid tumors. Thus, many antitumor strategies
targeting VEGF have been developed to inhibit
cancer angiogenesis, offering hope successful
treatment of solid cancers. However, there are a
number of issues such as harmful effects on normal
vascularity in clinical trials. Taking this into
consideration, we employed Cordyceps militaris as
an antitumor approach due to its biological safety in
vivo. The herbal medicinal mushroom Cordyceps
militaris has been reported to show potential
anticancer properties including anti-angiogenic
capacity; however, its concrete properties have yet
to be fully demonstrated. In this study, we aimed to
elucidate the biological role of Cordyceps militaris
extract in tumor cells, especially in regulating
angiogenesis and growth of a human malignant
melanoma cell line. We demonstrated the
Cordyceps militaris extract to remarkably suppress
tumor growth via induction of apoptotic cell death
in culture, linked to abrogation of VEGF production
in melanoma cells. This was followed by mitigation
of Akt1 and GSK-3β activation, while p38α
phosphorylation levels were increased. Extract
treatment in a mouse model xenografted with
human melanoma cells resulted in a dramatic
antitumor effect with down-regulation of VEGF
expression. The results suggest that suppression of
tumor growth by Cordyceps militaris extract is, at
least, mediated by its anti-angiogenicity and
apoptosis induction capacities. Cordyceps militaris
extract may be a potent antitumor herbal drug for
solid tumors.
*1 Department of Cell Biology, Graduate School of
Medicine, Dentistry and Pharmaceutical Sciences,
*1
Department of Cell Biology, Graduate School of
Medicine, Dentistry and Pharmaceutical Sciences,
Okayama University
*2
Division of Cancer Biology, The Cancer Institute of
the Japanese Foundation for Cancer Research (JFCR)
*3
Department of Tumor Immunology, Aichi Medical
University School of Medicine
*4 Department of Respiratory Medicine, Okayama
University Hospital
Fig. 1. Schematic representation of biological
effects of CAR (Coksackie and adenovirus
receptor) on Rho A-associated kinase. Moderate
suppression of ROCK activity by CAR facilitates
growth, invasion and metastasis of SCC cells.
This work was published in “Oncogene” March
18, 2013.
12
Fig. 2. Treatment with C. militaris extract reduced
growth
of
subcutaneously
xenografted
melanomas. (A) Gross appearance of xenografted
tumors. Tumors with subcutaneous melanoma
tissues were excised from mice after 37 days with
or without C. militaris extract treatment. Compared
to the control group, C. militaris -treated mice
showed small tumors. (B) Histology (H&E staining)
and immunohistochemistry of excised tumors of
mice treated with C. militaris or saline (control).
Expression of VEGF on tumor cells and
morphology of vascular vessels in tumor tissues
stained by CD31 mAb are shown. Both VEGF and
CD31
expression
were
reduced
in
C.
militaris-treated
tumors.
(C)
Growth
of
subcutaneously xenografted melanomas in mice
after treatment with C. militaris or saline. Mice
bearing subcutaneous MeWo xenografts were
treated with saline or the supernatant of C.
militaris after tumor volumes had reached ∼ 100
mm3 (day 1). Tumor-bearing mice in each group
were subjected to subcutaneous administration of
the supernatant or saline once every two days for
37 days consecutively. Tumor volumes were
measured daily from day 1 to day 37. Statistical
significance of tumor volumes and that of tumor
masses were evaluated by Student’s t-tests. Saline
(n=3, mean volume of 2101 mm3 on day 37) vs. C.
militaris (n=3, mean volume 384 mm3 on day 37);
*P=0.069 >0.05. Final masses of tumors excised on
day 37 in each group are also shown in the graph
(right). Saline (n=3, mean weight of 874 mg) vs. C.
militaris (n=3, mean weight of 230 mg); **P=0.031
<0.05. Means and SE (standard error) of triplicates
are shown.
3. Development of a New Rapid Isolation
Device for Circulating Tumor Cells (CTCs)
using 3D Palladium Filter and its
Application for Genetic Analysis
Yusa A, Toneri T, Masuda T, Ito S, Yamamoto S, Okochi
M, Kondo N, Iwata H, Yatabe Y, Ichinosawa Y, Kinuta S,
Kondo E, Honda H, Arai F, Nakanishi H.
Circulating tumor cells (CTCs) in the blood of
patients with epithelial malignancies provide a
promising and minimally invasive source for early
detection of metastasis, monitoring of therapeutic
effects and basic research addressing the
mechanisms of metastasis. In this study, we
developed a new filtration-based, sensitive CTC
isolation device, consisting of a 3-dimensional (3D)
palladium (Pd) filter with an 8 μm-sized pore in the
lower layer and a 30 μm-sized pocket in the upper
layer to trap CTCs on a filter micro-fabricated by
precise lithography plus electroforming processes.
This simple pump-less device driven by gravity
flow can enrich CTCs from whole blood within 20
min. After on-device staining of CTCs for 30 min,
the filter cassette was removed from the device,
fixed in a cassette holder and set up on an upright
fluorescence microscope. Enumeration and
isolation of CTCs for subsequent genetic analysis
were completed within 1.5 hr and 2 hr, respectively.
Cell spike experiments demonstrated that the
recovery rate of tumor cells from blood with this Pd
filter device was more than 85%. Single living
tumor cells were efficiently isolated from spiked
tumor cells by a micromanipulator, and KRAS
mutation, HER2 gene amplification and
overexpression, for example, were successfully
detected from such isolated single tumor cells.
Sequential analysis of blood from mice bearing
metastases revealed that CTC increased with
progression of metastasis. Furthermore, a
significant increase in the number of CTCs from the
blood of patients with metastatic breast cancer was
observed compared with patients without metastasis
and healthy volunteers. These results suggest that
this new 3D Pd filter-based device could be a useful
tool for rapid, cost effective and sensitive detection,
enumeration, isolation and genetic analysis of CTCs
from peripheral blood in both preclinical and
clinical settings.
13
proved difficult to accurately determine the organ
distribution of metastases. We thus developed a
multimodality imaging system by fusion of 3
dimensional (3D) fluorescence with MRI imaging
and demonstrated improved diagnostic accuracy
over either method alone.
The present results suggest that multimodality
imaging consisting of fluorescence imaging with
NIR-labeled EGFR or CEA antibodies and MRI
allows sensitive, specific and anatomically accurate
detection of peritoneal metastases at an early stage,
noninvasively.
Fig. 3. Detection and enumeration of CTC from
patients with breast cancers.
A-D Representative CTC cluster showing a
EpCAM+/CD45-/Hoechst33342+ pattern.
This work was published in PLOS ONE
11;9(2):e88821. 2014.
4.
New whole-body multimodality imaging
of gastric cancer peritoneal metastases
combining fluorescence imaging with
ICG-labeled antibodies and MRI in mice
Ito A, Ito Y, Matsushima S, Tsuchida D, Ogasawara M,
Hasegawa J, Misawa K, Kondo E, Kaneda N,
Nakanishi H.
Peritoneal metastasis is the most frequent
pattern of recurrence after curative surgery for
gastric cancer. However, such recurrence is difficult
to detect by conventional computed tomography
(CT) and magnetic resonance imaging (MRI) at an
early stage. To improve the sensitivity and
specificity of diagnostic imaging for peritoneal
metastases, here, we developed a new type of
multimodality imaging combining fluorescence
with near-infrared fluorophore (NIR)-labeled
antibodies and MRI. Dual optical imaging of
peritoneal metastases was carried out using
luciferase-tagged gastric cancer cell lines and
XenoLight
CF750
or
indocyanine-green
(ICG)-labeled anti-human EGFR or CEA antibodies
as probes in mice with an Ivis in vivo imaging
system. This whole-body fluorescent imaging
system sensitively and noninvasively detected
metastatic foci less than 1mm in diameter in the
peritoneal cavity. Fluorescence imaging proved to
be specific because fluorescence signals were
abolished by blocking with an excess amount of
unlabeled antibody. Although this fluorescence
imaging had higher sensitivity for detection of
small-sized peritoneal metastases than MRI, it
Fig. 4. Multimodality imaging with combination
of 3D optical imaging and MRI for peritoneal
metastases. Multimodality images constructed
by fusion of optical and MRI images.
This work was publicshed in Gastric Cancer
173(3), 497-507. 2014
14
From left to right
First row: Ms. Yuri Nishimura, Ms. Yumiko Suyama, Ms. Anna Ogiso, Dr. Yoshitaka Sekido,
Ms. Haruna Ikeda, Dr. Yuko Murakami-Tonami, Ms. Miwako Nishizawa
Second row: Mr. Yoshio Tatematsu, Dr. Kosuke Tanaka, Dr. Akihiro Matsushita, Dr. Taketo
Kato, Dr. Hirotaka Osada, Ms. Yumi Nakahama
Inset: Dr. Hiromi Furuta
15
Division
of Molecular Oncology
________________________________________________________________________________
Yoshitaka Sekido M.D., Ph.D., Chief
Hirotaka Osada, M.D., Ph.D., Section Head
Yutaka Kondo, M.D., Ph.D., Section Head (until April 2014)
Makiko Fujii, D.D.S., Ph.D., Senior Researcher (until August 2015)
Yuko Murakami-Tonami, M.D., Ph.D., Senior Researcher
Yoshio Tatematsu, B.S., Research Assistant
Miwako Nishizawa, B.P., Research Assistant
Haruna Ikeda, Semi-regular Employee (as of April 2014)
Yumi Nakahama, Semi-regular Employee
Research Resident
Fumiharu Ohka, M.D., Nagoya University Graduate School of Medicine (until June 2014)
Shuhei Hakiri, M.D., Nagoya University Graduate School of Medicine (until March 2015)
Akihiro Matsushita, M.D., Nagoya University Graduate School of Medicine (as of July 2014)
Taketo Kato, M.D., Nagoya University Graduate School of Medicine (as of April 2015)
Visiting Trainees
Hiromi Furuta, M.D., Nagoya City University Graduate School of Medicine
Akihiro Matsushita, M.D., Nagoya University Graduate School of Medicine (until June 2014)
Taketo Kato, M.D., Nagoya University Graduate School of Medicine (until March 2015)
Kosuke Tanaka, M.D., Nagoya University Graduate School of Medicine (as of April 2014)
Maiko Yoshida, M.D, Nagoya University Graduate School of Medicine (as of April 2015)
Eri Ikeda, Meijo University (until August 2015)
Anna Ogiso, Meijo University (as of August 2014)
Arisu Nimura, Kinjo Gakuin University (May~July 2014)
Mao Inayoshi, Kinjo Gakuin University (May~July 2014)
Yuri Nishimura, Kinjo Gakuin University (as of December 2015)
Yumiko Suyama, Kinjo Gakuin University (as of December 2015)
General Summary
Our goal is to determine genetic lesions and epigenetic alterations giving rise to human solid cancers and
use this information for prevention, diagnosis, and treatment of these diseases. Currently, we are focusing on
malignant mesothelioma and lung cancer. These studies also provide an opportunity to dissect biochemical
and pathological pathways of malignant phenotypes including deregulated cell proliferation, invasion,
metastasis and drug resistance. Human cancers arise because of genetic mutations in oncogenes and tumor
suppressor genes, and we are approaching the problem by study of candidate genes, systematic molecular
analysis of biochemical pathways, and global approaches such as microarray analysis of gene expression
profiles and next generation sequencing. Epigenetic changes featuring DNA methylation, histone
modification, and microRNA expression have also been identified not only as mechanisms of inactivation of
tumor suppressor genes but also as fundamental for regulated maintenance of cancer stem cell populations
and differentiated cell lineages in each tissue. We also functionally analyze candidate genes by transducing
wild type copies into human cancer cells and testing for their ability to suppress malignancy in vitro and in
vivo as well as characterizing their protein products biochemically. Alternatively, we inactivate their
expression using RNA interference (RNAi) in either tumor or normal cells and then study the resultant
phenotype. Understanding the functions of the genes mutated and the signaling pathways disrupted should
provide a foundation for a translational research approach to human malignancies, from bench to bedside.
16
1. Functional differences between wild-type
and mutant-type BAP1 tumor suppressor
against malignant mesothelioma cells
Hakiri, S., Osada, H., Ishiguro, F., Murakami, H.,
Murakami-Tonami, Y., Yokoi, K.*1, and Sekido, Y.
Malignant mesothelioma (MM) is an aggressive
neoplasm which is developed from the pleural or
peritoneal cavities. The BRCA1-associated protein
1 (BAP1) gene, which is located on chromosomal
3p21.1, has been shown to be frequently inactivated
in MM. BAP1 encodes a nuclear-localized
deubiquitinating enzyme with an NH2-terminal
ubiquitin COOH-terminal hydrolase domain and a
COOH-terminal domain which contains two
nuclear localization signals (Fig 1a).
Among the 19 cell lines that we established
from Japanese MM patients, we found BAP1
mutations in 5 cell lines (Fig 1a). To clarify the
inactivation mechanisms of the BAP1 mutants, we
first studied the subcellular localization of BAP1.
We demonstrated that the wild-type preferentially
resides in the nucleus of the cells but the mutant
BAP1 is excluded from the nucleus (Fig 2b).
Transduction of the wild-type BAP1 vector induced
both inhibition of cell proliferation and
anchorage-independent cell growth of MM cells
with BAP1-deletion, while BAP1 mutants of a
missense or C-terminal truncated form showed only
partial or no growth inhibitory effects. Next, we
studied whether or not BAP1 is involved in MM
cell survival after DNA damage. After irradiation
(IR), we detected that both wild-type and mutant
BAP1 were similarly phosphorylated and
phospho-BAP1 was localized mainly in the nucleus.
Interestingly, BRCA1 proteins were decreased in
the MM cells with BAP1 deletion, and that
transduction of the mutants as well as wild-type
BAP1 increased BRCA1 proteins, suggesting that
BAP1 may promote DNA repair partly through the
stabilization of BRCA1 protein. Additionally, using
the MM cells with BAP1 deletion, we found that
the wild-type, and even a missense mutant, BAP1
conferred a higher survival rate after IR compared
to the control vector. Our results indicated that,
while wild-type BAP1 suppresses MM cell
proliferation and restores cell survival after
IR-damage, some mutant BAP1 may also
moderately retain these functions.
Fig. 1. (a) BAP1 gene mutations in MM cell lines.
The five cell lines (Y-MESO-9, 14, 25, and 61,
and ACC-MESO-4) were established in our lab,
and two (NCI-H28 and H2452) were kindly
provided from Dr. Adi F. Gazdar.
(b) BAP1 mutation effects on its own nuclear
localization. Immunofluorescence analysis of
subcellular BAP1 localization was performed
after transduction of BAP1 vectors, and
percentages of subcellular localization of BAP1
were calculated.
2. SMC2 regulates the transcription of
DDR genes and shows synergistic
phenotype with MYCN
Murakami-Tonami, Y., Kishida, S.*1, Takeuchi, I.*2,
Katou, Y.*3, Maris, JM.*4, Ichikawa, H.*5, Kondo, Y.*6,
Sekido, Y., Shirahige, K.*3, Murakami, H.*7, and
Kadomatsu, K.*1
The condensin complex is required for
chromosome condensation during mitosis. It has
been reported that condensin complex also has a
role in interphase, but it is still not clear about its
role in interphase compared to mitosis.
Neuroblastoma is the most common extracranial
childhood tumor of sympathetic neuron. In human
neuroblastoma, MYCN amplification correlates
with poor prognosis.
Here we found that downregulation of SMC2
(structural maintenance of chromosome 2),
condensin complex subunit, and MYCN
amplification/overexpression showed synergistic
*1
Department of Thoracic Surgery, Nagoya University
Graduate School of Medicine, Nagoya, Japan
17
*1
Department of Molecular biology, Nagoya University
*2
Department of Computer Science/Scientific and
Engineering Simulation, Nagoya Institute of Technology
*3
Laboratory of Genome Structure & Function, Institute
of Molecular and Cellular Biosciences, The University of
Tokyo
*4
Department of Pediatrics and Center for Childhood
Cancer Research, Children's Hospital of Philadelphia,
University of Pennsylvania
*5
Division of Genetics, National Cancer Institute
*6
Department of Epigenomics, Nagoya City University
*7
Department of Biological Science, Faculty of Science
and Engineering, Chuo University
lethal response in human neuroblastoma cells.
SMC2
knockdown
in
MYCN
amplified/overexpressed
neuroblastoma
cells
induced DNA damage, leading to apoptosis. In
addition, we showed that SMC2 interacts MYCN
and transcriptionally regulates DNA damage
response (DDR) genes. Finally we showed that
patients bearing MYCN amplified tumors tend to
benefit from low SMC2 expression. Our results
identify novel function of SMC2 (or condensin
complex) in DDR and we proposed that SMC2 or
condensin complex is a potential molecular target
of MYCN-amplified neuroblastoma.
Fig. 2. (a) Knockdown of SMC2 induces DNA
damage
and
apoptosis.
Growth
of
MYCN-overexpressed SH-EP cells and control
SH-EP cells infected with non-target shRNA or
SMC2-specific shRNAs. Counting started 3 days
after infection. On each day, three plates were
counted and averaged. Data are shown as a
ratio of the number of cells at 3 days after
transfection and are represented as the mean ±
SD of n = 3 independent repeats. (b) SMC2
knockdown efficiency of (a). (c) The effects of
SMC4 (condensin subunit) expression on the
overall survival (OS) and event-free survival
(EFS) rates of patients bearing MYCN
high-expression and low-expression tumors.
Within each of the two tumor subsets
considered, those with expression levels of
each condensin subunit greater than the
median (blue or green line) were compared to
the remainder of the tumors in the subset (red
or purple line) using a Kaplan-Meier analysis.
18
From left to right
First row: Dr. M. Katayama, Ms. K. Hirano, Ms. Y. Kasugai, Dr. K. Matsuo, Dr. S. Tsuzuki, Dr.
T. Kakiuchi, Ms. I. Morikawa.
Second row: Dr. M. Sawabe, Dr. T. Ugai, Dr. H. Masaoka, Dr. T. Takahara, Ms. S. Sato.
19
Division
of Molecular Medicine
________________________________________________________________________________
Keitaro Matsuo, M.D., Ph.D., M.Sc. Chief
Shinobu Tsuzuki, M.D., Ph.D. Section Head
Miyuki Katayama, M.D., Ph.D. Senior Researcher
Yumiko Kasugai, B.S. Research Assistant
Taishi Takahara, M.D. Research Resident
Hiroyuki Masaoka, M.D. Research Resident
Kyoko Hirano, B.S. Research Assistant
Visiting Trainees
Noriaki Yoshida, M.D. Nagoya University Graduate School of Medicine (until June 2014)
Tatsuo Kakiuchi, M.D. Nagoya University Graduate School of Medicine
Tomotaka Ugai, M.D. Jichi Medical University Graduate School of Medicine
Michi Sawabe, M.D. Nagoya City University Graduate School of Medicine
General Summary
Research in this laboratory is focused on elucidating genetic and molecular bases of human cancer acting
in conjunction with environmental exposures, with a view to applying the obtained knowledge to clinical
oncology and prevention. Currently we are working on two aspects with physicians/researchers within and
outside Aichi Cancer Center, : 1) molecular epidemiology of cancer and it’s applications in clinical oncology
and prevention,; and 2) molecular biology on of hematological malignancies, with physicians/researchers
within and outside Aichi Cancer Center.
Sporadic cancers are consequences of molecular/genetic events after environmental exposure and it’s
combinationinteracting with the genetic background. Elucidating optimal combinations of environmental and
genetic factors is essential for targeted prevention and treatment. In collaboration with the Division of
Epidemiology and Prevention, we are trying to: (1) elucidate new gene-environment interactions ;between
genetic background and environmental factors, (2) development of risk prediction models integrating genetic
and environment factors, ; and (3) development of applications of developed models in both pre- and
post-clinical settings.
Hematological malignancies are highly associated with genetic changes so that some hematological
malignanciesexamples can be classified according to genetic changes specific to given disease entities. Such
close associations provides evidence that the genetic changes play pivotal roles in disease development
and/or clinicopathological manifestations. Over the last two years, we have studied several issues in
particular: (1) elucidation of combinatorial combination effects of genes involved in lymphomagenesis using
a newly established mouse lymphoma model; (2) establishment of a method to generate ATL-like neoplasms
in mice employing in vitro-induced T cells; (3) involvement of clonal heterogeneity in the development of
lymphoma and its impact on clinical outcome; (4) establishment of a model of YAP-driven malignant
mesothelioma.
1. Establishing prediction models of
upper-aerodigestive tract cancer using
molecular and environmental information
stratified by a combination of ALDH2 genotype
and alcohol consumption to aid the development of
personalized prevention. We conducted two ageand sex- matched case-control studies, one (630
cases and 1,260 controls) for model derivation and
the second (654 cases and 654 controls) for external
validation. Based on data from the derivation study,
a prediction model was developed by fitting a
conditional logistic regression model using the
following predictors: age, sex, smoking, drinking,
and ALDH2 genotype. The risk model, including a
combination of ALDH2 genotype and alcohol
consumption, provided high discriminatory
Koyanagi, Y.*1, Ito, H.*2, Oze, I.*2, Hosono, S.*2,
Watanabe, M.*2, Tanaka, H.*2, Abe, T.*3, Shimizu, Y.*3,
Hasegawa, Y.*4, and Matsuo, K.
Alcohol
consumption
and
aldehyde
dehydrogenase 2 (ALDH2) polymorphisms are
associated with upper-aerodigestive tract (UATC)
risk, and a significant gene-environment interaction
between the two has been confirmed in various
studies in Asia. We have developed a risk
prediction model and estimated absolute risks
20
singly-transduced with either Card11L232LI or
Bcl6 died during the same period of time. The
developed lymphomas expressed exogenously
expressed
Card11L232LI
and
Bcl6,
and
endogenous Irf4, which is a molecular hallmark of
activated B cell-like DLBCL, the most aggressive
subtype of DLBCL. These mouse models may help
elucidate the molecular mechanisms underlying B
cell neoplasms and may aid in the development of
effective therapeutic drugs.
accuracy and good calibration in both the derivation
and validation studies: C statistics were 0.82 (95%
confidence intervals 0.80–0.84) and 0.83
(0.81–0.85), respectively, and calibration plots of
both studies stayed close to the ideal calibration line.
Cumulative risks were obtained by combining odds
ratios estimated from the risk model with the
age-specific incidence rate and population size. For
heavy drinkers with a heterozygous genotype,
cumulative risk at age 80 was above 20%. In
contrast, risk in the other groups was less than 5%.
In conclusion, modification of alcohol consumption
according to ALDH2 genotype will have a major
impact on UATC prevention. These findings
represent a simple and practical model for
personalized cancer prevention.
*1
Third Department of Internal Medicine, Graduate
School of Medicine and Pharmaceutical Sciences,
University of Toyama, Toyama, Japan
*2
Department of Pathology, School of Medicine, Kurume
University, Kurume, Japan
3. Establishment of a new mouse model of
adult T cell leukemia
*1
Department of Preventive Medicine, Kyushu
University Faculty of Medical Sciences, Fukuoka, Japan
*2
Division of Epidemiology and Prevention, Aichi
Cancer Center Research Institute, Aichi, Japan
*3
Department of Gastrointestinal Surgery, Aichi Cancer
Center Central Hospital, Aichi, Japan
*4
Department of Head and Neck Surgery, Aichi Cancer
Center Central Hospital, Aichi, Japan
Division of Molecular Medicine
Kasugai-Maeda, Y., Yoshida, N.*1, Seto, M.*1, and
Tsuzuki, S.
Acute type adult T-cell leukemia (acute ATL)
develops in human T-cell leukemia virus type 1
(HTLV-1) carriers. Although the HTLV-1-encoded
HBZ gene is critically involved, HBZ alone is
insufficient, and cooperative additional “hits” are
required for the development of ATL. Candidate
cooperative hits are being delineated, but methods
to rapidly explore their roles in ATL development in
collaboration with HBZ are lacking. We present a
new mouse model of rapidly generated acute ATL
that features transplanting in vitro-induced T cells
retrovirally transduced with HBZ, and two
cooperative genes BCLxL and AKT, into mice. T
cells co-transduced with HBZ/BCLxL/AKT
allowed in vitro-generated T cells to grow in the
absence of cytokines (Flt3-ligand and IL-7), which
was not attainable with the use of any combination
of the two genes. Upon transplantation into mice,
although transplanted T cells were a mixture of
cells variously transduced with the three genes, the
tumors developing in the animals were composed of
HBZ/BCLxL/AKT-triply transduced T cells,
showing synergistic activity of the three genes.
The genetic/epigenetic landscape of ATL has only
recently been elucidated, and actual roles of the
elucidated “hits” in ATL pathogenesis remain to be
explored. Our model thus is important in providing
a versatile tool to explore roles of the hits in the
development of acute ATL, in collaboration with
HBZ.
2.
Generation of mouse models of
lymphoid neoplasms using retroviral gene
transduction of in vitro-induced germinal
center B cells
Takahara T., Arita, K.*1, Yoshida, N.*2, Sugiyama, T.*1,
Seto, M.*2, and Tsuzuki, S.
Evidence is accumulating that hematologic
malignancies develop following acquisition of
multiple genetic changes. Because of the
complexity of these genetic changes, the generation
of animal models is often laborious. In an effort to
circumvent this difficulty, we previously established
a mouse model by employing in vitro-induced
mouse germinal center (GC) B cells; the GC B cells
were induced in vitro, retrovirally transduced with a
combination of genes or mutated genes of interest,
and transplanted into mice. Using this model
system, we were able to generate diffuse large B
cell lymphoma (DLBCL) by a combination of Myc
and Bcl2. We also found that a combination of
Burkitt
lymphoma-associated
genes
Myc,
CCND3T283A, E47V557E, Akt and TCL1A
induced Burkitt-like lymphoma, and that a
combination of Card11L232LI and Bcl6 induced
DLBCL in mice. All mice receiving a transplant of
Card11L232LI/Bcl6 co-transduced GC B cells died
or developed lymphoma within two months after
transplantation, while none of a group of mice
receiving a transplant of GC B cells
*1
4.
21
Clonal
heterogeneity
of
lymphoid
malignancies
prognosis
correlates
with
K.*1, Yoshida, N.*2, Karube, K.*3, Katayama, M.,
Nakanishi, H.*4, Kiyono, T.*5, Nakamura, S.*6, Osada,
H.*7, Sekido, Y.*7, Seto, M.*2,8, and Tsuzuki, S.
poor
Katayama, M., Yoshida, N., Umino A.*1, Kato H.*2,
Tagawa, H.*3, Nakagawa, M.*4, Fukuhara, N.*5,
Sivasundaram, S.*6, Takeuchi, I.*7, Hocking TD.*8, Arita,
K., Karube, K., Tsuzuki. S, Nakamura, S.*9, Kinoshita
T.*2, and Seto, M.
Disruption of the Hippo pathway as a result of
deletion and/or mutation of the involved genes (e.g.,
neurofibromin 2 [NF2]) is frequently observed in
mesothelioma. The disruption results in reduced
phosphorylation of yes-associated protein (YAP),
the non-phosphorylated YAP translocating to the
nucleus and regulating gene expression. While roles
of the disrupted Hippo pathway in maintenance of
established tumors have been investigated using
mesothelioma cell lines, involvement in the
initiation of mesothelioma development remains
unclear.We have employed immortalized human
mesothelial cells to study the transformation
process, and found that NF2 knockdown led to
transformation of the cells concurrently with
reduction in YAP phosphorylation. The targeted
cells exhibited enhanced growth in vitro, and
formed tumors following transplantation into nude
mice. Similar results to those obtained by NF2
knockdown were also achieved using forced
expression of wild-type (wt) or constitutively active
(S127A) YAP. Although such directed expression of
YAPwt or YAPS127A was insufficient to transform
primary (unimmortalized) human mesothelial cells,
our findings provide evidence for crucial roles of
activated YAP in transformation of mesothelial cells.
To identify YAP-regulated genes critical for
mesothelial tumorigenesis, we conducted gene
expression analysis comparing control- and
YAP-transduced immortalized human mesothelial
cells. Gene Set Enrichment Analysis (GSEA) using
a gene set down-regulated by YAP knock-down in
mesothelioma cell lines revealed phospholipase C
beta 4 (PLCB4) to be among the top-ranking genes
up-regulated by YAP in our experiments. PLCB4
was up-regulated by YAP in immortalized human
mesothelial cells, and down-regulated by YAP
knock-down in YAP-driven mesothelioma cells.
shRNA-mediated silencing of PLCB4 attenuated
the growth of YAP-transduced mesothelial cells and
Hippo-disrupted, but not -proficient, mesothelioma
cell lines.
Our model system thus provides a versatile tool
to
investigate
mechanisms
underlying
mesothelioma development. We suggest that
PLCB4 may be an attractive drug target for
treatment of malignant mesothelioma.
Clonal heterogeneity in lymphoid malignancies
has been recently reported in adult T-cell
lymphoma/leukemia, peripheral T-cell lymphoma,
not otherwise specified, and mantle cell lymphoma.
We have extended analyses to other types of
lymphoma including marginal zone lymphoma,
follicular lymphoma, and diffuse large B-cell
lymphoma. To determine the presence of clonal
heterogeneity, 332 cases were examined using array
comparative genomic hybridization analysis.
Results showed that the incidence of clonal
heterogeneity varied from 25% to 69% among
different types of lymphoma. Survival analysis
revealed that mantle cell lymphoma and diffuse
large B-cell lymphoma with clonal heterogeneity
showed significantly poorer prognosis, and that
clonal heterogeneity was confirmed as an
independent predictor of poor prognosis for both
types of lymphoma. Interestingly, 8q24.1 (MYC)
gain, 9p21.3 (CDKN2A/ 2B) loss and 17p13 (TP53,
ATP1B2, SAT2, SHBG) loss were recurrent
genomic lesions among various types of lymphoma
with clonal heterogeneity, suggesting at least in part
that alterations of these genes may play a role in
clonal heterogeneity.
*1
Department of Hematology and Oncology, Mie
*2
Department of Hematology and Cell Therapy, Aichi
Cancer Center hospital, Nagoya, Japan;
*3
Department of Hematology, Nephrology, and
Rheumatology, Akita University Graduate School of
Medicine, Akita, Japan
*4
Lymphoid Malignancies Branch, Center for Cancer
Research, National Cancer Institute, USA
*5
Department of Hematology and Rheumatology, Tohoku
University Hospital, Sendai, Japan
*6
Department of Biochemistry, Aichi Medical University
School of Medicine, Nagakute, Japan
*7
Department of Computer Science/Scientific and
Engineering Simulation, Nagoya Institute of Technology,
Nagoya, Japan
*8
Department of Human Genetics, McGill University,
Montréal, Canada;
*9
Department of Pathology and Clinical Laboratories,
Nagoya University Hospital, Nagoya, Japan
*1
Third Department of Internal Medicine, Graduate
School of Medicine and Pharmaceutical Sciences,
University of Toyama, Toyama, Japan
*2
5. Establishment of a model of YAP-driven
malignant mesothelioma
Kakiuchi, T., Takahara, T., Kasugai-Maeda, Y., Arita,
22
*3
Department of Cytopathology, University of the
Ryukyus, Okinawa, Japan
*4
Laboratory of Pathology and Clinical Research, Aichi
Cancer Center, Aichi Hospital, Aichi, Japan
*5
Division of Virology National Cancer Center Research
Institute, Tokyo, Japan
*6
Department of Pathology and Clinical Laboratories,
Nagoya University Hospital, Aichi, Japan
*7
Division of Molecular Oncology, Aichi Cancer Center
Research Institute, Aichi, Japan
*8
Immuno-Biological Laboratories Co., Ltd, Gunma,
Japan
23
From left to right
First raw: Dr. K. Kuwahara, Dr. K. Kuzushima, Dr. R. Ohta
Second raw: Ms. R. Terada, Dr. N. Gondo, Ms. K. Hiramatsu, Dr. A. Demachi-Okamura
Inset: Dr. Y. Akatsuka, Dr. Y. Uemura, Dr. R. Zhang, Ms. M. Tatsumi
24
Division
of Immunology
________________________________________________________________________________
Kiyotaka Kuzushima, M.D. Chief
Kazuhiko Kuwahara, M.D. Section Head (as of April 2014)
Ayako Demachi-Okamura, Ph.D. Researcher
Rieko Ohta, Ph.D. Researcher (as of January 2015)
Rong Zhang, Ph.D. Research Resident (until March 2015)
Eri Yamada, M.D. Research Resident (until March 2014)
Naomi Gondo, M.D. Research Resident (as of April 2014)
Haruru Kotani, M.D. Research Resident (as of April 2015 until September 2015)
Kaho Hiramatsu, Research Assistant
Rie Terada, Semi-regular Employee
Minako Tatsumi, Semi-regular Employee (until March 2015)
Keiko Shiraishi, Semi-regular Employee
Tomiko Tsuboi, Semi-regular Employee
Hitomi Asai, Semi-regular Employee (as of January 2014)
Visiting Researcher
Yoshiki Akatsuka, M.D. Department of Hematology & Oncology, Fujita Health University
Yasushi Uemura, D.D.S. Division of Cancer Immunology, Exploratory Oncology Research & Clinical Trial
Center, National Cancer Center (until March 2015)
Visiting Trainees
Hiroyuki Maki, Department of Cellular Oncology, Nagoya University Graduate School of Medicine (until
March 2014)
Norihiro Ueda, M.D. Department of Hematology and Oncology, Nagoya University Graduate School of
Medicine (until March 2015)
General Summary
The object of our research is to establish molecular and cellular bases for novel cancer therapy taking
advantage of immune responses. In addition, studies of breast cancer have been initiated as of 2014 to focus
on development of future immunotherapy for this very common disease. The achievements during past two
years were as follows.
Firstly, we reported an interesting HLA-Cw7-binding peptide that cross-reacts with an
HLA-A24-restricted CTL clone established from naïve CD8+ T lymphocytes stimulated with the
HLA-A24-expressing TOV21G, an ovarian cancer cell line. The peptide is derived from the cellular protein,
RBM4, binds to HLA-Cw7 molecules and mediates allo-reactivity. To our knowledge, this is the first
peptide presented by an HLA-Cw allele and recognized by HLA-A24-restricted T-cells.
Secondly, we have researched human telomerase reverse transcriptase (hTERT) as an attractive target
antigen for cancer immunotherapy due to its expression in the vast majority of human tumors. We previously
established an HLA-A24-restricted and hTERT461-469-specific T cell clone and demonstrated the utility of the
T cell epitope for cancer immunotherapy. TCRα/β genes from the clone were transduced into CD8+ T cells
from healthy adults to build a model of adoptive immunotherapy using TCR gene-modified T cells. To
enhance the tumoricidal effects, we tried to use invariant NKT (iNKT) cells as a cellular adjuvant.
Thirdly, we applied Yamanaka factors to reprogram human iNKT cells to pluripotency and then regenerated
Vα24 invariant, TCR-expressing T lymphocytes in vitro. The regenerated iNKT (re-iNKT) cells
demonstrated proliferation and IFN-γ production in response to α-galactosylceramide. They induced
dendritic cell maturation and downstream activation of cancer antigen-specific cytotoxic T lymphocytes, and
exhibited NKG2D- and DNAM-1-mediated natural killer cell-like cytotoxicity against cancer cell lines. In
addition to the unlimited supply from induced pluripotent stem cells, the cellular adjuvant properties and a
newly identified cytotoxic feature of these re-iNKT cells offer potential for development of effective
immunotherapies against cancer.
25
Lastly, we investigated the expression of DSS1 (deleted in split-hand/split-foot malformation 1) and
chemosensitivity using DSS1-overexpressed and -knockdown breast cancer cells. Interestingly,
DSS1-overexpressed cells did not show any proliferative changes, but became more resistant to
chemotherapy. On the other hand, DSS1-depletion increased chemosensitivity. A similar phenotype was also
observed using camptothecin, etoposide, doxorubicin, paclitaxel, and cisplatin. This result indicates that
DSS1 depletion confers a drug sensitive trait against anti-cancer chemotherapy independently of BRCA2.
*1
Department of Gynecologic Oncology, Aichi Cancer
Center Hospital
*2
Department of Obstetrics and Gynecology, Nagoya
1. Identification of a naturally processed
HLA-Cw7-binding peptide that cross-reacts
with
HLA-A24-restricted
ovarian
cancer-specific CTLs
Demachi-Okamura, A., Yamada, E., Kondo, S.*1, Shibata,
K.*2, Kikkawa, F.*2, and Kuzushima, K.
2. Interaction of V α 24 iNKT cells with
dendritic cells increases the therapeutic
efficacy of TCR-gene modified T cells
Cytotoxic T lymphocytes (CTLs) can exert
anti-tumor effects through recognition of tumor
antigen-derived peptides bound to human leukocyte
antigens (HLAs) on cell surfaces. This recognition
activates T-cell receptors (TCR). CTLs to probe
such peptides are important reagents to define
tumor antigens but generating tumor-specific CTLs
usually requires autologous tumor cell lines. We
have successfully induced cancer-specific CTLs
using artificial antigen presenting cells (aAPCs)
that have endogenous tumor-associated peptides on
given HLA molecules but not their own HLAs.
We report here an HLA-A24-restricted CTL
clone, which was established from naïve CD8+ T
lymphocytes stimulated with aAPCs derived from
TOV21G, an ovarian cancer cell line. The CTL
clone responded not only to ovarian cancer cells in
the context of HLA-A24 but also to allogeneic
HLA-Cw7 molecules through cross-reactive TCR
recognition. Using the cDNA expression cloning
method, the CTL clone alloreacted, this being
mediated through a nine-mer peptide derived from
the TOV21G cellular protein, RBM4. The epitope
peptide presented by HLA-A24 cells has yet to be
identified. The CTL was demonstrated to be
monoclonal on account of single positivity in
tetramer
staining,
indicating
that
the
HLA-A*24:02-restricted
tumor-specific
clone
recognizes the epitope peptide presented by
allo-HLA-Cw*07:02 in a cross-reactive manner.
Moreover, the clone showed a requirement for
peptides presented by HLA-Cw7 and the specificity
for peptides was vague, implying that the TCR
featured polyspecific alloreactivity.
To our knowledge, these results provide the first
evidence of allorecognition of an HLA-Cw allele by
HLA-A-restricted
T-cells.
They
suggest
allorecognition in certain HLA combinations, and
further study is now needed to understand the
mechanisms of alloreactivity to improve the
prediction of alloresponses in clinical settings.
Zhang, R., Uemura, Y.*1, Liu, T.*2, Ikeda, H.*3, Okamoto,
S.*4, Tatsumi, M., Mineno, J.*4, Shiku, H.*3, and
Kuzushima, K.
Adoptive
immunotherapy
using
TCR
gene-modified T cells is an attractive strategy for
targeting cancer. Human telomerase reverse
transcriptase (hTERT) is a promising target antigen
for cancer immunotherapy due to its expression in
vast majority of human tumors. We previously
established
a
HLA-A24-restricted
and
hTERT461-469-specific T cell clone and demonstrated
the utility of the T cell epitope for cancer
immunotherapy (Int J Cancer 110: 403-412). In the
current study, TCRα/β genes from this T cell clone
were transduced with CD8+ T cells and their
anti-tumor potential was analyzed. The redirected T
cells efficiently expressed the transduced TCRs and
killed hTERT peptide-loaded T2-A24 cells, but
never exhibited cytotoxicity against lung cancer
cells expressing both HLA-A24 and hTERT. To
address this issue, we used invariant NKT (iNKT)
cells, a unique subset of T cells that recognize
α-GalCer presented by CD1d on antigen-presenting
cells, as a cellular adjuvant. We found that soluble
factors from the iNKT cell/α-GalCer-dendritic cell
(DC) interaction enhanced the HLA-I expression on
cancer cells, thereby increasing susceptibility to cell
lysis. In addition, the soluble factors upregulated
both perforin and granzyme B in redirected T cells,
in turn enhancing the potency of cellular immunity.
Furthermore, in vivo transfer of redirected T cells in
combination with iNKT/α-GalCer-DC inhibited
tumor growth and significantly prolonged survival
in a xenograft model. Thus, the additional transfer
of iNKT/α-GalCer-DC may improve the efficacy of
redirected T cells.
*1
Division of Cancer Immunotherapy, Exploratory
Oncology Research & Clinical Trial Center, National
Cancer Center, Kashiwa.
*2
Cancer Center, Chinese PLA General Hospital., Beijing,
26
China.
*3
Department of Immuno-Gene Therapy, Mie University
Graduate School of Medicine, Mie.
*4
Center for Cell and Gene Therapy, Takara Bio Inc.,
Shiga.
cancer cells highly-sensitive to anti-cancer
drugs through DNA damage
Gondo, N., Rezano A.*1, Ohta, R., Kuzushima, K.,
Toyama, T.*2, and Kuwahara, K.
Breast cancer is a leading cause of cancer death
of women all over the world. Genetic BRCA1/2
insufficiency is associated with breast cancer
development, but germline mutations of the two
genes have been only rarely observed in sporadic
breast cancers, which account for approximately
95% of the total. Some reports have indicated that
overexpression of BRCA2 significantly correlate
with poor survival and worse histological findings;
however, the contribution of BRCA2 to
tumorigenesis or malignant progression in sporadic
breast cancers still remains controversial.
DSS1
(deleted
in
split-hand/split-foot
malformation 1), a mammalian component of the
transcription/mRNA export complex, has been
shown to interact with and stabilize BRCA2. We
initially investigated the expression level of DSS1
mRNA using 289 samples derived from patients
with sporadic breast cancers, and classified into
DSS1high and DSS1low groups. Although no
significant differences were observed between the
groups for several parameters such as nodal status
and nuclear grade, the DSS1high group showed a
significant shorter survival in relapse-free survival
curves, while the difference in the breast
cancer-specific survival curve was not significant.
These results were supported by the public database
of Kaplan-Meier, designated KMplotter.
In order to clarify the significance of DSS1
levels in patient prognosis, in vitro studies using
DSS1-overexpressed and -knockdown breast cancer
cells were performed. DSS1-overexpressed cells
did not show any proliferative changes, but became
more resistant to chemotherapy. On the other hand,
DSS1-depletion increased chemosensitivity. A
similar phenotype was also observed using
camptothecin, etoposide, doxorubicin, paclitaxel,
and cisplatin. DSS1 has some binding partner such
as BRCA2, 26S proteasome subunits, and TREX2
component PCID2.
We speculated that increased chemosensitivity
by DSS1 depletion might be affected by BRCA2
insufficiency; however, BRCA2 knockdown
showed marginal effects on chemosensitivity. This
result indicates that DSS1 depletion confers a drug
sensitive trait for anti-cancer chemotherapy
independently of BRCA2.
3. Cellular adjuvant properties and direct
cytotoxicity in rejuvenated Vα24 invariant
NKT cells from human induced pluripotent
stem cells
Zhang, R., Kitayama, S.*1, Liu, R.*2, Ueda, N., Tatsumi,
M., Kaneko, S.*1, Kuzushima, K., and Uemura, Y.*3
Vα24 invariant natural killer T (iNKT) cells are
a small subset of T lymphocytes implicated in the
regulation of a broad range of immune responses.
They recognize specific lipid antigens presented by
CD1d on antigen-presenting cells and induce both
innate and adaptive immune responses. Their
powerful adjuvant properties, which enhance
effective immunity against cancer, means that they
represent promising therapeutic tools. However, this
has been hampered by the difficulty of preparing
functional iNKT cells from patients in large enough
numbers to be therapeutic. To overcome this
obstacle, we used Yamanaka factors to reprogram
human iNKT cells to pluripotency and then
regenerated Vα24 invariant, TCR-expressing T
lymphocytes in vitro through optimized α-chain
cytokine combination. Like the parental iNKT cells,
the regenerated iNKT (re-iNKT) cells showed
proliferation and IFN-γ production in response to
α-galactosylceramide (α-GalCer). The re-iNKT
cells also induced dendritic cell maturation and
downstream activation of cancer antigen-specific
cytotoxic T lymphocytes in vitro, and exhibited
NKG2D- and DNAM-1-mediated natural killer
cell-like cytotoxicity against cancer cell lines. In
addition to their availability in an unlimited supply
from induced pluripotent stem cells, the cellular
adjuvant properties and a newly identified cytotoxic
feature of these re-iNKT cells offer the potential for
development of effective immunotherapies against
cancer.
*1
Shin Kaneko Laboratory, Department of Cell Growth
and Differentiation, Center for iPS cell Research and
Application (CiRA), Kyoto University, Kyoto.
*2
Cancer Center, Chinese PLA General Hospital., Beijing,
China.
*3
Division of Cancer Immunotherapy, Exploratory
Oncology Research & Clinical Trial Center, National
Cancer Center, Kashiwa.
4. Depletion of DSS1, which is a member
of mammalian TREX2 complex and
maintains BRCA2 stability, confers breast
*1
Department of Anatomy and Cellular Biology,
Universitas Padjadjaran, Bandung, Indonesia.
*2
Department of Oncology, Immunology and Surgery,
27
Nagoya City University Graduate School of Medical
Sciences.
28
From left to right
First row: Ms. R. Watanabe, Dr. C. Oneyama, Ms. M. Miyata
Second row: Mr. Y. Ninomiya, Dr. T. Kanda, Mr. A. Kuwahara
Inset: Dr. S. Nakasu
29
Division
of Microbiology and Oncology
________________________________________________________________________________
Chitose Oneyama, Ph.D. Chief (as of April 2015)
Teru Kanda, M.D. Section Head
Sho Nakasu, PhD. Senior Researcher
Daisuke Kawashima, Ph.D. Research Resident (until March 2014)
Yohei Narita, Research Assistant (until March 2014)
Mamiko Miyata, Research Assistant (as of April 2014)
Risayo Watanabe, Semi-regular employee (as of November 2015)
Visiting Trainee
Yuichi Ninomiya, Graduate Student, Graduate School of Science, Osaka University
Atsushi Kuwahara, Graduate Student, Graduate School of Science, Osaka University
General Summary
In the Division of Microbiology and Oncology, we seek to understand the mechanisms
maintaining cellular homeostasis and their dysfunction in cancer. Normal cellular homeostasis
requires the coordinated regulation of signaling molecules in terms of space, time and quantity.
Accumulation of genetic and epigenetic alterations or oncogenic viral infection may disrupt the
stringent regulation of signaling networks and lead to cellular transformation and tumor progression.
Our studies involve dissecting genes, proteins, and signaling mechanisms directly responsible for
oncogenic phenotypes and identifying novel therapeutic targets. Currently, the goals of our research
are to elucidate the molecular mechanisms underlying aberrant activation of Src pathways in a wide
variety of human cancer cells and EBV (Epstein-Barr virus)-driven oncogenesis. During the period
2014-2015, our research interest was concentrated on the following issues: 1) Spatial regulation of
Src via lipid rafts controls cancer progression; 2) microRNA-mediated gene expression controls
Src-related oncogenic signaling; 3) clustered microRNAs of the Epstein-Barr virus cooperatively
downregulate an epithelial cell-specific metastasis suppressor; and 4) a herpesvirus specific motif of
Epstein-Barr virus DNA polymerase is required for efficient lytic genome synthesis.
1. Spatial regulation of Src via lipid rafts
controls cancer progression
activation was required for tumorigenesis and
invasiveness in some cancer cells featuring c-Src
upregulation. We propose that the Src–Fer axis
represents a new therapeutic target for treatment of
a subset of human cancers.
Oneyama, C., Kuwahara, A., Miyata, M., and Watanabe,
R.
c-Src is upregulated in various human cancers,
suggesting roles in development and progression of
malignancies. However, the molecular circuits of
c-Src oncogenic signaling remain elusive. We have
shown that a Fer tyrosine kinase oligomer mediates
and amplifies Src-induced tumor progression.
Previously, we found that transformation of
fibroblasts is promoted by the relocation of c-Src to
non-raft membranes. Under these conditions, we
identified Fer and ezrin as non-raft c-Src targets.
c-Src directly activated Fer by initiating its
autophosphorylation, which was further amplified
by Fer oligomerization. Fer interacted with active
c-Src at focal adhesion membranes and activated
Fer-phosphorylated
ezrin
to
induce
cell
transformation. Fer also proved crucial for cell
transformation induced by v-Src or epidermal
growth-factor receptor activation. Furthermore, Fer
2. MicroRNA-mediated gene expression
controls Src-related oncogenic signaling
Oneyama, C., Ninomiya, Y., Miyata, M., and Watanabe,
R.
The cellular Src (c-Src) tyrosine kinase is
upregulated and believed to play a pivotal role in
various human cancers. However, the molecular
mechanisms underlying c-Src-mediated tumor
progression remain elusive. Recent studies have
revealed that several microRNAs (miRNAs)
function as tumor suppressors by regulating the
malignancy-associated expression of signalling
molecules. Aberrant expression of miRNAs is
frequently observed in human cancers and should
be exploited to seek related molecular targets. We
have focused on miRNAs found to be involved in
30
3. Clustered microRNAs of the EpsteinBarr virus cooperatively downregulate an
epithelial
cell-specific
metastasis
suppressor
Src signalling in various cancers.
We found that among the c-Src-regulated
microRNAs (miRNAs), miR-27b is also repressed
by activation of K-Ras ⁄ H-Ras. Inhibitor studies
suggested that the phosphatidylinositol 3-kinase
pathway is involved in the repression of miR-27b, a
characteristic of various colon cancer cell lines and
tumor tissues. Re-expression of miR-27b in human
colon cancer HCT116 cells caused morphological
changes and suppressed tumor growth, cell
adhesion, and invasion. We also identified
ARFGEF1 and paxillin as novel targets of miR-27b,
and established that miR-27b-mediated regulation
of ARFGEF1 is crucial for controlling
anchorage-independent growth. We could further
show that paxillin is important for controlling cell
adhesion and invasion. Re-expression of miR-27b
suppressed the activation of c-Src induced by
integrin-mediated cell adhesion, suggesting that
repression of miR-27b may contribute to c-Src
activation in cancer cells.
These findings provide strong evidence that
miR-27b functions as a tumor suppressor by
controlling ARFGEF1 and the paxillin ⁄ c-Src
circuit at focal adhesions. Thus, we continue our
focus on Src-related miRNAs, their target genes,
mechanisms behind their interplay and their
implications for cancer therapeutics.
Kanda, T., and Miyata, M.
The Epstein-Barr virus (EBV) encodes its own
microRNAs (miRNAs); however, their biological
roles remain elusive. The commonly used EBV
B95-8 strain lacks a 12-kb genomic region, known
as the BamHI A rightward transcripts (BART)
locus, where a number of BART miRNAs are
encoded. Here, bacterial artificial chromosome
(BAC) technology was used to generate an EBV
B95-8 strain in which the 12-kb region was fully
restored at its native locus [BART(+) virus].
Epithelial cells were stably infected with either the
parental B95-8 virus or the BART(+) virus, and
BART miRNA expression was shown to be
successfully reconstituted in the BART(+)
virus-infected cells. Microarray analyses of cellular
gene expression identified N-myc downstream
regulated gene 1 (NDRG1) as a putative target of
BART miRNAs. The NDRG1 protein was barely
expressed in B cells, highly expressed in epithelial
cells, including primary epithelial cells, and
strongly downregulated in BART(+) virus-infected
epithelial cells of various origins. Although in vitro
reporter assays identified BART22 as responsible
for the NDRG1 downregulation, EBV genetic
analyses revealed that BART22 was not solely
involved; rather, the entire BART miRNA cluster 2
was responsible for the downregulation.
Immunohistochemical analyses revealed that the
NDRG1 protein level was downregulated
significantly in EBV-positive nasopharyngeal
carcinoma specimens. Considering that NDRG1
encodes an epithelial differentiation marker and a
suppressor of metastasis, these data imply a
causative relationship between BART miRNA
expression and epithelial carcinogenesis in vivo.
Fig. 1. When active c-Src is liberated from lipid
rafts, c-Src has close access to Fer in non-raft
membranes, e.g. focal adhesions, triggering Fer
autoactivation via direct phosphorylation and
amplification by oligomerization of Fer, which in
turn
induces
tumor
progression
by
phosphorylation of downstream effectors such as
ezrin.
Fig. 2. In situ hybridization (ISH) analyses of EBER
expression (left panels) and immunohistochemical
analyses of NDRG1 expression (right panels) in
nasopharyngeal carcinoma biopsy specimens.
Note NDRG1 downregulation in EBER-ISH-positive
specimens.
Representative
images
of
EBER-ISH-negative (top) and EBER-ISH-positive
(bottom) specimens are shown.
31
4. A herpesvirus specific motif of
Epstein-Barr virus DNA polymerase is
required for efficient lytic genome
synthesis
Narita, Y., Kawashima, D., Kanda, T., Tsurumi, T., and
Murata, T.
The Epstein-Barr virus (EBV) is associated with
several malignancies, including the Burkitt’s
lymphoma and the nasopharyngeal carcinoma. To
avoid such disorders, understanding the molecular
mechanisms of EBV replication is important. The
EBV DNA polymerase (Pol) is one of the essential
factors for viral lytic DNA replication. Although it
is well known that its C-terminal half, possessing
DNA polymerase and 3'-5' exonuclease activity, is
highly conserved among Family B Pols, the
NH2-terminal half has yet to be characterized in
detail. In this study, we show that a stretch of
hydrophobic
amino
acids
within
the
pre-NH2-terminal domain of EBV Pol plays an
important role. In addition, we could identify the
most essential residue for replication in the motif.
These findings should shed light on molecular
mechanisms of viral DNA synthesis and help in
development of new herpesvirus treatments.
32
From left to right
First row: Dr. R. Kajino, Dr. T. Fujishita, Dr. M. Aoki, Dr. Y. Kojima, Dr. K. Sakuma
Second row: Ms. H. Tamaki, Ms. Y. Itoh, Ms. N. Saito, Ms. F. Orim, Ms. Y. Goto, Ms. K.
Kobori
33
Division
of Molecular Pathology
________________________________________________________________________________
Masahiro Aoki, M.D., D.M.Sc., Chief
Keiichiro Sakuma, M.D., D.M.Sc., Senior Researcher
Yasushi Kojima, M.D., D.M.Sc., Senior Researcher
Rie Kajino., Ph.D. Researcher (as of April 2012)
Teruaki Fujishita, D.M.Sc Researcher (as of April 2013)
Yoshiko Goto, D.V.M.S., Research Assistant
Noriko Saito, Research Assistant
Kyoko Kobori, Research Assistant
Yumiko Ito, Research Assistant
Florence Orim, M.D., D.M.Sc., Research Resident (as of April 2014)
Visiting Scientists
Reiji Kannagi, M.D., D.M.Sc.
Visiting Trainees
Yukie Fuma, Kinjo Gakuin University
Mark van Boxtel, Radboud University Nijmegen (until February 2014)
Ryota Mitsuya, Aichi Gakuin University (as of April 2014 until March 2015)
Adam Douglas, Queen’s University Belfast (as of July 2015 until August 2015)
General Summary
The incidence of colorectal cancer is increasing steadily in Japan and the disease is predicted to become
the most common cancer as of 2020. Accumulating evidence suggests that in addition to genetic and
epigenetic changes in the genome of cancer cells, interactions with non-cancer stromal cells play essential
roles in support of colorectal cancer progression.
Our research has been primarily aimed at identifying novel molecular targets for prevention and/or
therapy of colorectal cancer through detailed analyses of intestinal tumor progression in genetically
engineered mouse models, followed by evaluation of the findings using clinical samples. We are currently
focusing on the following subjects: (1) Clarifying the roles of tumor microenvironment in cancer formation
and progression; (2) Elucidating the molecular mechanisms of metastasis; and (3) Unraveling the
pathophysiology of cancer cachexia.
1. An in vivo shRNA screen identifies
HNRNPLL as a novel colorectal cancer
metastasis suppressor
by PCR for sequencing, followed by identification
of the candidate genes targeted by the shRNA.
Among 47 candidate genes identified, we focused
on
Hnrnpll
(heterogeneous
nuclear
ribonucleoprotein L-like) gene encoding a
pre-mRNA binding protein involved in pre-mRNA
splicing. Hnrnpll knockdown in CMT93 cells
significantly increased their matrigel invasion in
vitro and lung metastasis in vivo, which could be
cancelled by introducing an shRNA-resistant
Hnrnpll
cDNA.
Interestingly,
an
RNA-immunoprecipitation analysis identified Cd44
as a candidate target of Hnrnpll, and the mRNA
level of Cd44 variant 6 (Cd44v6), a splicing variant
of Cd44 that had been shown to demarcate colon
cancer stem cells driving colon cancer metastasis,
was increased by knocking down Hnrnpll in colon
cancer cells. Furthermore, treatment with
anti-CD44v6 monoclonal antibody suppressed
Sakuma, K., Sasaki, E., Kimura, K., Komori, K.,
Shimizu, Y., Yatabe, Y., and Aoki, M.
Despite the recent advances in treatment of
colorectal cancer, the prognosis is unfavorable for
patients with distant metastases. With an attempt to
identify novel targets for prevention and/or therapy
of colorectal cancer metastasis, we performed a
functional in vivo shRNA library screen for
metastasis suppressor genes using an orthotopic
transplantation model. CMT93 cells, a murine
colorectal cancer cell line with poor metastasizing
activity, were transduced with Venus fluorescent
protein and lentiviral shRNA library, and then
transplanted into the rectum of C57/BL6 mice.
Genomic DNA was collected from metastatic
lesions, and the integrated shRNA were retrieved
34
suppression sensitizes them to EGFR inhibition.
Our findings may provide a rationale for
combination therapy with EGFR inhibitors and
mTOR kinase inhibitors for colon cancer patients.
matrigel invasion of colon cancer cells induced by
Hnrnpll knockdown in vitro, suggesting that
Hnrnpll may suppress invasion and metastasis, at
least in part, by modulating the alternative splicing
of Cd44. To gain further insights into the
involvement of HNRNPLL in colorectal cancer
invasion and metastasis, we examined its
expression
during
epithelial-mesenchymal
transition (EMT), and found that EMT induction
reduced the HNRNPLL level in SW480 cells. The
link between HNRNPLL and EMT was further
suggested by immunostaining analysis of clinical
samples; colorectal cancer cells with low
E-cadherin expression at the invasion front
exhibited decreased HNRNPLL expression as
compared with those in the tumor center. These
results suggest that HNRNPLL is a novel metastasis
suppressor in colorectal cancer.
*1
Department of Pharmacology, Graduate School of
Medicine, Kyoto University
3. The MEK/ERK signaling inhibition
suppresses intestinal polyp formation by
reducing the stromal COX-2 and CCL2
levels
Fujishita, T., Kajino, R., Kojima, Y., Taketo, MM.*1, and
Aoki, M.
Frequent mutations in the KRAS gene in colon
cancer suggest that inhibition of the MEK/ERK
signaling can benefit colon cancer patients.
However, the precise roles of the signaling in
intestinal tumor formation remain to be elucidated.
We found that the MEK/ERK signaling was
frequently activated in stromal cells, such as
vascular endothelial cells and fibroblasts, rather
than in adenoma epithelial cells in intestinal polyps
of ApcΔ716 mice. Treatment with the MEK inhibitor
trametinib suppressed intestinal polyp formation,
accompanied by reduced adenoma cell proliferation
and angiogensis. Trametinib treatment reduced the
cyclooxgenase-2 (COX-2) level both in primary
cultures of intestinal fibroblasts and in ApcΔ716
polyps. Moreover, the level of chemokine (C-C
motif) ligand 2 (CCL2), a chemokine implicated in
formation of Apc mutant polyps, was reduced in
fibroblasts treated in vitro with trametinib or the
COX-2 inhibitor rofecoxib, as well as in the polyps
of trametinib-treated ApcΔ716 mice. These results
suggest that the stromal MEK/ERK signaling
promotes intestinal polyp expansion through
production of COX-2, which can up-regulate the
pro-inflammatory chemokine CCL2.
2. Simultaneous inhibition of mTOR and
EGFR suppresses invasion of intestinal
adenocarcinoma in cis-Apc+/Δ716 Smad4+/mice
Fujishita, T., Kojima, Y., Kajino, R., Taketo, MM.*1, and
Aoki, M.
Activation of the mechanical target of
rapamycin (mTOR) signaling is implicated in
various human cancers. We previously reported that
activation of mTOR complex 1 (mTORC1) was
required for expansion of adenomatous polyps that
developed in the intestines of Apc+/ △ 716 mice.
However, the roles of the mTOR signaling in
invasive intestinal adenocarcinomas have remained
elusive. Treatment of cis-Apc+/ △ 716/Smad4+/–
(cis-Apc/Smad4) mice, a mouse model of
locally-invasive intestinal adenocarcinoma, with the
mTORC1 inhibitor everolimus significantly
suppressed expansion of their tumors. Moreover,
the ATP-competitive mTOR kinase inhibitor
AZD8055 suppressed the growth of intestinal
adenocarcinomas more potently than everolimus.
However, both everolimus and AZD8055 failed to
reduce the depth of tumor invasion. Western-blot
and immunohistochemistry analyses revealed
activation of EGFR and its downstream signaling in
the AZD8055-resistant tumors. Although single
treatment with the EGFR inhibitor erlotinib showed
little inhibitory effects on adenocarcinoma
formation in cis-Apc/Smad4 mice, combination
treatment with AZD8055 and erlotinib strongly
suppressed both the expansion and invasion of the
adenocarcinomas. These results suggest that
feedback activation of EGFR is involved in the
resistance of invasive intestinal adenocarcinomas
against mTOR inhibition in vivo, and that mTOR
*1
Department of Pharmacology, Graduate School of
Fig.1. Schematic representation of the roles of
the stromal MEK/ERK signaling in intestinal
adenoma formation in Apc mutant mice.
35
The front cover of Cancer Science highlighting
the work by Fujishita T et al (3).
Immunofluorescence staining for p-ERK (green)
and vimentin (mesenchymal cell marker, red) in
small intestinal polyps of Apc Δ 716 mice using
confocal lase scanning microscopy. Nuclei are
stained with DAPI (blue).
36
From left to right
First row: Ms. Y. Takada, Dr. S. Era, Ms. K. Kobori, Dr. H. Goto, Ms. N. Tanigawa
Second row: Dr. H. Tanaka, Dr. H. Inaba, Dr. M. Inagaki, Ms. E. Kawamoto, Dr. K. Kasahara,
Dr. I. Izawa, Dr. Y. Hayashi, Dr. A. Inoko
Inset: Dr. M. Matsuyama, Dr. D. He, Dr. Z. Wang, Ms. C. Yuhara, Ms. Y. Itoh, Dr. P. Li
37
Division
of Biochemistry
________________________________________________________________________________
Masaki Inagaki, M.D., Ph.D. Chief
Ichiro Izawa, M.D., Ph.D. Section Head
Hidemasa Goto, M.D., Ph.D. Section Head
Akihito Inoko, M.D., Ph.D. Senior Researcher
Kousuke Kasahara, Ph.D. Researcher
Yuko Hayashi, Ph.D. Research Assistant
Hiroki Tanaka, D.D.S. Ph.D. Research Resident
Hironori Inaba, Ph.D. Research Resident
Hiroyuki Makihara, Research Resident (as of April 2015)
Saho Era, Ph.D. Research Resident (until September 2014)
Kyoko Kobori, Semi-regular Employee (until December 2014)
Eriko Kawamoto, Semi-regular Employee
Naomi Tanigawa, Semi-regular Employee
Visiting Scientists
Hiromasa Aoki, Graduate School of Pharmaceutical Sciences, Nagoya City University
Hiroyuki Makihara, Graduate School of Dentistry, Aichi Gakuin University (as of April 2015)
General Summary
Tetraploidy, a state in which cells have doubled chromosomal sets, is observed in ~20% of solid tumors
and is considered to frequently precede aneuploidy in carcinogenesis. Tetraploidy is also detected during
tissue differentiation and with aging processes. We have generated knock-in mice featuring vimentin with
mitotic phosphorylation-defective mutations to impair cytokinesis. Homozygotic (VIMSA/SA) mice presented
with cataracts and impaired wound healing. We found that some subcutaneous tetraploid fibroblasts caused
by cytokinetic failure enter a new cell cycle and then develop into aneuploid fibroblasts in vivo, which
promotes premature aging. We therefore suggest that tetraploidy without genetic alteration of cancer-related
genes may be associated with premature aging rather than carcinogenesis.
Non-motile primary cilia are microtubule-based sensory organelles that regulate a number of signaling
pathways during development and tissue homeostasis. Tumor cells are known to often lack primary cilia, but
whether their loss is directly linked to tumorigenesis is completely unclear. We have recently found that
ubiquitin-proteasome machinery removes trichoplein, a negative regulator of ciliogenesis, from mother
centrioles and thereby causes Aurora-A inactivation, leading to ciliogenesis. We have identified KCTD17 as
a substrate-adaptor for Cul3-RING E3 ligases (CRL3s) that polyubiquitylates trichoplein. Depletion of
KCTD17 specifically arrests ciliogenesis at the initial step of axoneme (ciliary microtubule doublet)
extension through aberrant trichoplein-Aurora-A activity. These results strongly indicate that the ubiquitin
proteasome pathway is critically involved in the regulation of primary cilia formation.
1. Ndel1 is a suppressor of primary cilia
assembly
reassembly is suppressed by trichoplein-mediated
Aurora-A activation in growing cells. We found that
Ndel1, a well-known modulator of dynein activity,
localizes at the subdistal appendage of the mother
centriole, which nucleates a primary cilium. In the
presence of serum, Ndel1 depletion reduced
trichoplein at the mother centriole and induced
unscheduled primary cilia formation, which was
reversed by forced trichoplein expression or
co-knockdown of KCTD17 (an E3 ligase
component protein for trichoplein). Serum
starvation induced transient Ndel1 degradation,
subsequent to the disappearance of trichoplein at
the mother centriole. Forced expression of Ndel1
Inaba, H., Goto, H., Kasahara, K., Inoko, A., He, D.,
Tanigawa, N., Hayashi, Y., Kobori, K., Kumamoto, K.*1,
Yonemura, S.*2, Goshima, N.*3, Yamano S.*4, Wanibuchi,
H.*4, Kiyono, T.*5, Hirotsune, S.*1, and Inagaki, M.
The primary cilium projects from cell surfaces
and is considered to function as a chemo- and/or a
mechano-sensor. Dysfunction of a primary cilium is
associated with a broad spectrum of diseases such
as polydactyly, obesity and polycystic kidney
disease. In addition, loss of cilia is associated with
various types of cancer.
We previously showed that primary cilia
38
serum starvation-induced ciliogenesis. Using
protein array and siRNA screens, we identified
KCTD17 as a substrate adaptor for Cul3-RING E3
ligase (CRL3) that polyubiquitylates trichoplein.
SiRNA-mediated KCTD17 depletion prevented
trichoplein degradation and inactivation of
Aurora-A, thereby leading to defective ciliogenesis
after serum starvation. These phenotypes were
rescued by expression of siRNA-resistant
Myc-tagged KCTD17 or co-silencing of trichoplein,
and recapitulated by expression of non-degradable
trichoplein mutant. Similar to KCTD17 loss, Cul3
depletion also blocked ciliogenesis and trichoplein
degradation.
These
results
indicate
that
CRL3KCTD17 ubiquitin E3 ligase promotes
ciliogenesis by destroying trichoplein.
Maintenance of normal trichoplein levels is
essential for cell cycle progression through
regulating ciliogenesis, as excessive trichoplein
suppresses
unscheduled
ciliogenesis
in
non-proliferating cells, whereas its depletion leads
to unscheduled ciliogenesis in proliferating cells.
Our study revealed that UPS controls degradation
of trichoplein to promote ciliogenesis. We propose
that UPS deficiency serves as a potential underlying
mechanism of ciliogenesis, and that UPS regulation
might provide a novel means of ciliopathy
treatment.
suppressed trichoplein degradation and axonemal
microtubule extension during ciliogenesis, similar
to trichoplein induction or KCTD17 knockdown.
Most importantly, the proportion of ciliated and
quiescent cells was increased in kidney tubular
epithelia of newborn Ndel1-hypomorphic mice. In
addition, we found obesity in Ndel1-hypomorphic
mice, which is frequently observed in cilia-related
diseases. Thus, Ndel1 acts as a novel upstream
regulator of the trichoplein-Aurora-A pathway to
inhibit primary cilia assembly. These findings pave
the way for future studies evaluating the importance
of cilia dynamics in carcinogenesis.
Departments of *1Genetic Disease Research and
*4
Molecular Pathology, Osaka City University Graduate
School of Medicine
*2
RIKEN Center for Life Science Technologies
(Ultrastructural Research Team)
*3
Molecular Profiling Research Center for Drug
Discovery (molprof), National Institute of Advanced
Industrial Science and Technology (AIST)
*5
Division of Carcinogenesis and Cancer Prevention,
National Cancer Center Research Institute
2.
The
ubiquitin-proteasome
system
controls primary cilia formation at the initial
step of axoneme extension
Kasahara, K., Aoki H., Kawamoto E., Kawakami Y.*1,
Kiyono T.*2, Kawamura Y.*3, Goshima N.*1, and Inagaki
M.
*1
Discovery, National Institute of Advanced Industrial
Science and Technology
*2
*3
Japan Biological Informatics Consortium (JBiC)
Non-motile primary cilia are microtubule-based
sensory organelles that regulate a number of
signaling pathways during development and tissue
homeostasis. Defects in primary cilia formation
(ciliogenesis) result in numerous diseases and
disorders commonly known as ciliopathies. Primary
cilia are grown from modified centrioles called
basal bodies in response to cell cycle exit or entry
into quiescence, and this process is achieved
through coordinated interactions between positive
and negative regulators of ciliogenesis. However,
the regulatory mechanisms of ciliogenesis remain to
be determined in detail.
The ubiquitin-proteasome system (UPS)
controls most aspects of cell physiology including
cell cycling and organelle biogenesis. In this study,
we identified a newly recognized role of the UPS in
ciliogenesis. Using human RPE1 (telomerase
reverse transcriptase-immortalized retinal pigment
epithelia) cells, we could show that proteasome
activity is essential for ciliogenesis and destruction
of trichoplein, a centriolar protein that negatively
regulates ciliogenesis through activation of
Aurora-A kinases. Trichoplein is rapidly degraded
in a polyubiquitylation-dependent fashion during
3.
Cytokinetic failure induces aneuploidy
and aging in vimentin
Tanaka, Hir., Goto, H., Inoko, A., Hayashi, Y., Kobori, K.,
Tanigawa, N., Makihara, H., Izawa, I., and Inagaki, M.
Intermediate filaments (IFs), together with
microtubules and actin filaments, form the
cytoskeletal framework in the cytoplasm of
eukaryotic cells. Distinct from the other two major
cytoskeletal networks, IF component proteins are
divided into six groups and their composition
depends on tissue type and differentiation step.
Vimentin, a type III IF protein conserved in
vertebrate evolution, is expressed in all
mesenchymal cells and highly in lens tissue.
There is increasing evidence that IF
disassembly is regulated by phosphorylation of
Ser/Thr residues in the amino-terminal head
domains of IF proteins. Site- and phosphorylation
state-specific antibodies that can recognize a
phosphorylated residue and its flanking sequence
39
IF-bridge formation, binucleation (tetraploidy), and
extra-centrosome
formation
were
observed
specifically in VIMSA/SA fibroblasts. These
cellular structures disappeared with decreased
vimentin expression, leading to increased numbers
of aneuploid fibroblasts. Subsequently, VIMSA/SA
fibroblasts exhibited a significant elevation of
major
senescence-related
markers.
These
abnormalities resulted in impaired wound healing,
one premature aging phenotype.
are powerful tools to demonstrate site
(domain)-specific IF phosphorylation in cells.
Using these antibodies, we first showed that mitotic
IF phosphorylation is regulated by distinct protein
kinases in a spatiotemporally regulated manner.
Further detailed studies revealed that several
mitotic kinases such as Aurora-B, Cdk1, Plk1, and
Rho-kinase, participate in mitotic phosphorylation
of type III IF proteins. On transient expression of
type III IF proteins mutated at these mitotic
phosphorylation sites to Ala in type III IF-deficient
T24 cell line, we found that disturbance of mitotic
IF phosphorylation induced an abnormal IF
structure (referred to as an IF bridge) connecting
two daughter cells during the cytokinetic process.
These findings indicated that mitotic IF
phosphorylation is essential for efficient separation
of IFs into two daughter cells. Cells with an IF
bridge appeared to make two distinct decisions
regarding cell fate. The IF bridge was often torn off
the
two
daughter
cells,
likely
by
cell-adhesion-dependent traction force, resulting in
the completion of cytokinesis. With the other type
cells failed in cytokinesis, resulting in formation of
binucleate (multinucleate) cells. However, the
significance of mitotic IF phosphorylation during
organogenesis and tissue homeostasis remains
largely unknown.
In a previous study, we generated knock-in mice
expressing vimentin that harbors mutations in
mitotic phosphorylation sites. Homozygotic mice
(VIMSA/SA) presented with microophthalmia and
lens cataracts, whereas heterozygotic mice
(VIMWT/SA) were indistinguishable from the wild
type (VIMWT/WT) . In VIMSA/SA mice, lens
epithelial cells were reduced in number and
exhibited chromosomal instability (CIN), featuring
binucleation and aneuploidy. Electron microscopic
analyses revealed that lens fiber cells of VIMSA/SA
mice exhibited membrane disorganization similar to
defects in age-related cataracts. Since the mRNA
level of the senescence (aging)-related gene was
significantly elevated in the lens of VIMSA/SA, the
lens phenotypes in VIMSA/SA suggested a possible
causal relationship between CIN and premature
aging.
In our present study, we addressed whether
binucleate tetraploidy precedes aneuploidy or
whether these events occur independently by
analyzing dorsal skin wound healing in VIMSA/SA
mice. In response to skin injury, vimentin
expression was elevated in wound areas of
subcutaneous fibroblasts in a genotype-independent
manner. During the acute phase of wound healing
when vimentin expression was relatively high,
4.
Novel
platform
centrosomal functions
for
integrating
Inoko, A., Hayashi, Y., Kiyono, T.*1, Goshima, N.*2, and
Inagaki, M.
Centrosomes are small but exhibit dynamic
conformational changes during cell proliferation
and differentiation, featuring self-duplication,
spindle pole formation and primary cilia assembly.
Diseases related to centriolar abnormalities have
been reported, like microcephaly, malformations
and ciliopathies. Also, cancer cells are believed to
lack primary cilia. Our past findings are that (1)
forced ciliation results in cell cycle exit even in
growing media and (2) an endogenous mechanism
for primary cilia kinetics is the switching of
centriolar Aurora-A mitotic kinase activity through
trichoplein. These findings gave us the idea that the
centrosome might be a novel therapeutic target. In
fact, Aurora-A knockdown is effective for cultured
cancer cell-specific mitotic defects due to the lack
of the ability to form primary cilia.
Our subsequent screening of novel targets that
regulate centriolar dynamics is ongoing. Regarding
our previous finding of a protein with similarity to
trichoplein, we have now established its localization
on centrosomes and relations to both centriolar
duplication and spindle pole separation. With its
antibodies and exogenous expression, precise
centriolar localization at proximal edges and on
mother centriole-specific distal appendages,
responsible for integrating centrosomal function,
proved possible. Its knockdown cells failed to
demonstrate any of the following centrosomal
functions: ciliation, centriolar duplication and
spindle pole separation. Investigations are
continuing to provide more precise understanding
of phenomena and the underlying molecular
mechanisms.
*1
*2
Discovery, National Institute of Advanced Industrial
Science and Technology
40
From left to right
Dr. M. Inagaki, Dr. H. Kumimoto, Mr. Y. Minoura, Mr. Y. Nishikawa, Ms. Y. Shinohara,
and Dr. H. Nakamura
41
Central
Service Unit
________________________________________________________________________________
Masaki Inagaki, M.D. Chief
Hiroshi Kumimoto, Ph.D. Senior Researcher
Yasushi Minoura, B.P., Research Assistant (until March 2015)
Yukiko Nakai, B.P., Research Assistant (as of April 2015)
Yasushi Minoura, B.P., Senior Research Assistant (as of April 2015)
Hiromu Nakamura, D.M.Sc. Senior Semi-regular Research Assistant
Yasuhiro Nishikawa, Semi-regular Employee
Yoshimi Shinohara, Semi-regular Employee
Naomi Tanigawa, Semi-regular Employee
Visiting Trainees
Erika Ito, M.D. School of Medicine, Nagoya City University (until March 2014)
General Summary
Our main research project is molecular epidemiologic analysis of human esophageal cancer. In particular,
we have focused on the relationship between numbers of polymorphisms in the D-loop region of
mitochondrial DNA (mtDNA) and risk of esophageal cancer development.
1. Relationship between risk of esophageal
cancer and the number of polymorphisms
in mitochondrial DNA
expected to increase the risk of introducing
mutations into mtDNA and nuclear genomic DNA.
In accordance, we analyzed the number of
polymorphisms in mtDNA as a surrogate marker for
ROS level, then evaluating the relationship with
risk of esophageal cancer.
We performed sequencing analysis of D-loop
region in mtDNA using DNA samples from
esophageal cancer subjects and non-cancer controls
collected in the HERPACC study. At first, we
used re-sequencing primers sets created by ABI,
mitoSEQr. We found that the whole D-loop
region could be sequenced with 4 of 8 primer sets
of mitoSEQr. After sequencing the whole D-loop
region, we identified polymorphisms by comparing
these sequences with the common mtDNA
sequence.
So far, we have completed analyses of
polymorphisms in 66 subjects with esophageal
cancer and 67 non-cancer controls (see Table 1).
After analyses of polymorphisms in 185 esophageal
cancer patients and 185 non-cancer controls, we
will evaluate the relationship between esophageal
cancer risk and numbers of mitochondrial
polymorphisms.
Kumimoto, H.
Mitochondria are well known as the organelles
in eucaryotes responsible for production of energy
for cells and also they have well-defined roles in
apoptosis.
Recently, frequent mutations in
mitochondrial DNA (mtDNA) have been found in
various types of cancer, such as breast cancer and
stomach cancer.
Our previous analysis of
mutations in the D-loop region of mtDNA in
esophageal tumors demonstrated frequent somatic
mutations (in 34 % of cases). We also determined
nuclear genomic instability, but did not find any
correlation with somatic mtDNA mutations,
suggesting that instability of mtDNA in esophageal
cancer might be independent of nuclear genomic
instability.
Energy as ATP is produced in mitochondria with
reactive oxygen species (ROS) as by-products.
Polymorphisms in the genes related to proteins of
oxidative phosphorylation may thus elevate ROS
production by leaking electrons. Therefore, the
number of polymorphisms in mtDNA may
influence ROS levels in cells, which would be
Table 1. Summary of analyses of
polymorphism in mtDNA
Data are shown as average numbers / subject
except 'number of subjects analyzed'.
42
Librarians
________________________________________________________________________________
From left to right
Mr.T.Matsunaga, Ms.T.Yasuda, Ms.M.Sasanuma, Ms.M.Namura
43
Publications
______________________________________________________________________________________
Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber,
RP, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM,
Permuth-Wey, J, Pike, MC, Poole, EM, Risch, HA,
Rosen, B, Rossing, MA, Rothstein, JH, Rudolph,
A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB,
Schernhammer, E, Schwaab, I, Shu, XO, Shvetsov,
YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC,
Spiewankiewicz, B, Sucheston-Campbell, L, Teo,
SH, Terry, KL, Thompson, PJ, Thomsen, L,
Tangen, IL, Tworoger, SS, van Altena, AM,
Vierkant, RA, Vergote, I, Walsh, CS,
Wang-Gohrke, S, Wentzensen, N, Whittemore, AS,
Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo,
YL, Yang, H, Zheng, W, Ziogas, A, Kelemen, LE,
Berchuck, A, Georgia Chenevix-Trench on behalf
of the, Amg, Schildkraut, JM, Ramus, SJ, Goode,
EL, Monteiro, AN, Gayther, SA, Narod, SA,
Pharoah, PD, Sellers, TA, Phelan, CM.
Epithelial-Mesenchymal Transition (EMT) Gene
Variants and Epithelial Ovarian Cancer (EOC) Risk.
Genet Epidemiol, 2015. (PMID: 26399219)
Journals
J001. Ali, AM, Schmidt, MK, Bolla, MK, Wang,
Q, Gago-Dominguez, M, Castelao, JE, Carracedo,
A, Garzon, VM, Bojesen, SE, Nordestgaard, BG,
Flyger, H, Chang-Claude, J, Vrieling, A, Rudolph,
A, Seibold, P, Nevanlinna, H, Muranen, TA,
Aaltonen, K, Blomqvist, C, Matsuo, K, Ito, H,
Iwata, H, Horio, A, John, EM, Sherman, M,
Lissowska, J, Figueroa, J, Garcia-Closas, M,
Anton-Culver, H, Shah, M, Hopper, JL,
Trichopoulou, A, Bueno-de-Mesquita, B, Krogh,
V, Weiderpass, E, Andersson, A, Clavel-Chapelon,
F, Dossus, L, Fagherazzi, G, Peeters, PH, Olsen,
A, Wishart, GC, Easton, DF, Borgquist, S,
Overvad, K, Barricarte, A, Gonzalez, CA, Sanchez,
MJ, Amiano, P, Riboli, E, Key, T, Pharoah, PD.
Alcohol consumption and survival after a breast
cancer diagnosis: a literature-based meta-analysis
and collaborative analysis of data for 29,239 cases.
Cancer Epidemiol Biomarkers Prev, 23: 934-945,
2014. (PMID: 24636975)
J003.
Arita, K., Tsuzuki, S., Ohshima, K.,
Sugiyama, T., Seto, M.: Synergy of Myc, cell cycle
regulators and the Akt pathway in the development
of aggressive B-cell lymphoma in a mouse model.
Leukemia, 28: 2270-2272, 2014. (PMID:
25034145)
J002.
Amankwah, EK, Lin, HY, Tyrer, JP,
Lawrenson, K, Dennis, J, Chornokur, G, Aben,
KK, Anton-Culver, H, Antonenkova, N, Bruinsma,
F, Bandera, EV, Bean, YT, Beckmann, MW,
Bisogna, M, Bjorge, L, Bogdanova, N, Brinton,
LA, Brooks-Wilson, A, Bunker, CH, Butzow, R,
Campbell, IG, Carty, K, Chen, Z, Chen, YA,
Chang-Claude, J, Cook, LS, Cramer, DW,
Cunningham,
JM,
Cybulski,
C,
Dansonka-Mieszkowska, A, du Bois, A, Despierre,
E, Dicks, E, Doherty, JA, Dork, T, Durst, M,
Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB,
Fasching, PA, Fridley, BL, Gao, YT,
Gentry-Maharaj, A, Giles, GG, Glasspool, R,
Goodman, MT, Gronwald, J, Harrington, P,
Harter, P, Hasmad, HN, Hein, A, Heitz, F,
Hildebrandt, MA, Hillemanns, P, Hogdall, CK,
Hogdall, E, Hosono, S, Iversen, ES, Jakubowska,
A, Jensen, A, Ji, BT, Karlan, BY, Jim, H, Kellar,
M, Kiemeney, LA, Krakstad, C, Kjaer, SK,
Kupryjanczyk, J, Lambrechts, D, Lambrechts, S,
Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J,
Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu,
K, Lubinski, J, Lundvall, L, Massuger, LF,
Matsuo, K, McGuire, V, McLaughlin, JR,
McNeish, I, Menon, U, Milne, RL, Modugno, F,
Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U,
J004.
Asai, H., Fujiwara, H., Kitazawa, S.,
Kobayashi, N., Ochi, T., Miyazaki, Y., Ochi, F.,
Akatsuka, Y., Okamoto, S., Mineno, J.,
Kuzushima, K., Ikeda, H., Shiku, H., Yasukawa,
M.: Adoptive transfer of genetically engineered
WT1-specific cytotoxic T lymphocytes does not
induce renal injury. J Hematol. Oncol., 7:3, 2014.
(PMID: 24393438)
J005.
Bargagna-Mohan, P., Lei, L., Thompson,
A., Shaw, C., Kasahara, K., Inagaki, M., Mohan,
R.:
Vimentin
phosphorylation
underlies
myofibroblast sensitivity to withaferin A in vitro
and during corneal fibrosis. PLoS One, 17:
e0133399, 2015. (PMID: 26186445)
J006.
Brenner, DR, Amos, CI, Brhane, Y,
Timofeeva, MN, Caporaso, N, Wang, Y, Christiani,
DC, Bickeboller, H, Yang, P, Albanes, D, Stevens,
VL, Gapstur, S, McKay, J, Boffetta, P, Zaridze, D,
Szeszenia-Dabrowska, N, Lissowska, J, Rudnai, P,
Fabianova, E, Mates, D, Bencko, V, Foretova, L,
44
production. Carcinogenesis, 35: 164-72, 2014.
(PMID: 23917077)
Janout, V, Krokan, HE, Skorpen, F, Gabrielsen,
ME, Vatten, L, Njolstad, I, Chen, C, Goodman, G,
Lathrop, M, Vooder, T, Valk, K, Nelis, M,
Metspalu, A, Broderick, P, Eisen, T, Wu, X,
Zhang, D, Chen, W, Spitz, MR, Wei, Y, Su, L, Xie,
D, She, J, Matsuo, K, Matsuda, F, Ito, H, Risch, A,
Heinrich, J, Rosenberger, A, Muley, T,
Dienemann, H, Field, JK, Raji, O, Chen, Y,
Gosney, J, Liloglou, T, Davies, MP, Marcus, M,
McLaughlin, J, Orlow, I, Han, Y, Li, Y, Zong, X,
Johansson, M, Investigators, E, Liu, G, Tworoger,
SS, Le Marchand, L, Henderson, BE, Wilkens, LR,
Dai, J, Shen, H, Houlston, RS, Landi, MT,
Brennan, P, Hung, RJ. Identification of lung
cancer
histology-specific
variants
applying
Bayesian
framework
variant
prioritization
approaches within the TRICL and ILCCO consortia.
Carcinogenesis, 36: 1314-1326, 2015. (PMID:
26363033)
J010.
Chihara, D, Ito, H, Izutsu, K, Hattori, M,
Nishino, Y, Ioka, A, Matsuda, T, Ito, Y. Advance
and stagnation in the treatment of patients with
lymphoma and myeloma: Analysis using
population-based cancer registry data in Japan from
1993 to 2006. Int J Cancer, 137: 1217-1223, 2015.
(PMID: 25694231)
J011. Chihara, D, Ito, H, Katanoda, K, Shibata,
A, Matsuda, T, Sobue, T, Matsuo, K. Incidence of
myelodysplastic syndrome in Japan. J Epidemiol,
24: 469-473, 2014. (PMID: 25088696)
J012.
Chihara, D, Ito, H, Matsuda, T, Shibata,
A, Katsumi, A, Nakamura, S, Tomotaka, S,
Morton, LM, Weisenburger, DD, Matsuo, K.
Differences in incidence and trends of
haematological malignancies in Japan and the
United States. Br J Haematol, 164: 536-545, 2014.
(PMID: 24245986)
J007.
Cai, Q, Zhang, B, Sung, H, Low, SK,
Kweon, SS, Lu, W, Shi, J, Long, J, Wen, W, Choi,
JY, Noh, DY, Shen, CY, Matsuo, K, Teo, SH, Kim,
MK, Khoo, US, Iwasaki, M, Hartman, M,
Takahashi, A, Ashikawa, K, Matsuda, K, Shin,
MH, Park, MH, Zheng, Y, Xiang, YB, Ji, BT,
Park, SK, Wu, PE, Hsiung, CN, Ito, H, Kasuga, Y,
Kang, P, Mariapun, S, Ahn, SH, Kang, HS, Chan,
KY, Man, EP, Iwata, H, Tsugane, S, Miao, H,
Liao, J, Nakamura, Y, Kubo, M, Consortium,
DG-O, Delahanty, RJ, Zhang, Y, Li, B, Li, C, Gao,
YT, Shu, XO, Kang, D, Zheng, W. Genome-wide
association analysis in East Asians identifies breast
cancer susceptibility loci at 1q32.1, 5q14.3 and
15q26.1. Nat Genet, 46: 886-890, 2014. (PMID:
25038754)
J013.
Chihara, D, Ito, H, Matsuo, K.
Comparison of the incidence and trends of
hematologic malignancies between Japan and the
United States. Rinsho Ketsueki, 56: 366-374, 2015.
(PMID: 25971266)
J014.
Chihara, D, Izutsu, K, Kondo, E, Sakai,
R, Mizuta, S, Yokoyama, K, Kaneko, H, Kato, K,
Hasegawa, Y, Chou, T, Sugahara, H, Henzan, H,
Sakamaki, H, Suzuki, R, Suzumiya, J. High-dose
chemotherapy with autologous stem cell
transplantation
for
elderly
patients
with
relapsed/refractory diffuse large B cell lymphoma: a
nationwide retrospective study. Biol Blood Marrow
Transplant, 20: 684-689, 2014. (PMID: 24492141)
J008.
Camargo, MC, Kim, WH, Chiaravalli,
AM, Kim, KM, Corvalan, AH, Matsuo, K, Yu, J,
Sung, JJ, Herrera-Goepfert, R, Meneses-Gonzalez,
F, Kijima, Y, Natsugoe, S, Liao, LM, Lissowska, J,
Kim, S, Hu, N, Gonzalez, CA, Yatabe, Y,
Koriyama, C, Hewitt, SM, Akiba, S, Gulley, ML,
Taylor, PR, Rabkin, CS. Improved survival of
gastric cancer with tumour Epstein-Barr virus
positivity: an international pooled analysis. Gut, 63:
236-243, 2014. (PMID: 23580779)
J015. Chihara, D, Kagami, Y, Kato, H, Yoshida,
N, Kiyono, T, Okada, Y, Kinoshita, T, Seto, M.
IL2/IL-4, OX40L and FDC-like cell line support
the in vitro tumor cell growth of adult T-cell
leukemia/lymphoma. Leuk Res, 38: 608-612, 2014.
(PMID: 24679586)
J016.
Chornokur, G, Lin, HY, Tyrer, JP,
Lawrenson, K, Dennis, J, Amankwah, EK, Qu, X,
Tsai, YY, Jim, HS, Chen, Z, Chen, AY,
Permuth-Wey, J, Aben, K, Anton-Culver, H,
Antonenkova, N, Bruinsma, F, Bandera, EV,
Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L,
Bogdanova, N, Brinton, LA, Brooks-Wilson, A,
J009.
Chew, SH., Okazaki, Y., Nagai, H.,
Misawa, N., Akatsuka, S., Yamashita, K., Jiang, L.,
Yamashita, Y., Noguchi, M., Hosoda, K., Sekido,
Y., Takahashi, T., Toyokuni, S.: Cancer-promoting
role of adipocytes in asbestos-induced mesothelial
carcinogenesis through dysregulated adipocytokine
45
of Hereditary, B, Ovarian, C, Arnold, N, Brauch,
H, Hamann, U, Chang-Claude, J, Khan, S,
Nevanlinna, H, Ito, H, Matsuo, K, Bogdanova, NV,
Dork, T, Lindblom, A, Margolin, S, kConFab, AI,
Kosma, VM, Mannermaa, A, Tseng, CC, Wu, AH,
Floris, G, Lambrechts, D, Rudolph, A, Peterlongo,
P, Radice, P, Couch, FJ, Vachon, C, Giles, GG,
McLean, C, Milne, RL, Dugue, PA, Haiman, CA,
Maskarinec, G, Woolcott, C, Henderson, BE,
Goldberg, MS, Simard, J, Teo, SH, Mariapun, S,
Helland, A, Haakensen, V, Zheng, W,
Beeghly-Fadiel, A, Tamimi, R, Jukkola-Vuorinen,
A, Winqvist, R, Andrulis, IL, Knight, JA, Devilee,
P, Tollenaar, RA, Figueroa, J, Garcia-Closas, M,
Czene, K, Hooning, MJ, Tilanus-Linthorst, M, Li,
J, Gao, YT, Shu, XO, Cox, A, Cross, SS, Luben, R,
Khaw, KT, Choi, JY, Kang, D, Hartman, M, Lim,
WY, Kabisch, M, Torres, D, Jakubowska, A,
Lubinski, J, McKay, J, Sangrajrang, S, Toland,
AE, Yannoukakos, D, Shen, CY, Yu, JC, Ziogas, A,
Schoemaker, MJ, Swerdlow, A, Borresen-Dale,
AL, Kristensen, V, French, JD, Edwards, SL,
Dunning, AM, Easton, DF, Hall, P,
Chenevix-Trench, G. Polymorphisms in a Putative
Enhancer at the 10q21.2 Breast Cancer Risk Locus
Regulate NRBF2 Expression. Am J Hum Genet, 97:
22-34, 2015. (PMID: 26073781)
Bunker, CH, Butzow, R, Campbell, IG, Carty, K,
Chang-Claude, J, Cook, LS, Cramer, DW,
Cunningham,
JM,
Cybulski,
C,
Dansonka-Mieszkowska, A, du Bois, A, Despierre,
E, Dicks, E, Doherty, JA, Dork, T, Durst, M,
Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB,
Goodman, MT, Gronwald, J, Harrington, P,
Harter, P, Hein, A, Heitz, F, Hildebrandt, MA,
Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono,
S, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY,
Kelemen, LE, Kellar, M, Kiemeney, LA, Krakstad,
C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D,
Lambrechts, S, Le, ND, Lee, AW, Lele, S,
Leminen, A, Lester, J, Levine, DA, Liang, D, Lim,
BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L,
Massuger, LF, Matsuo, K, McGuire, V,
McLaughlin, JR, McNeish, I, Menon, U, Milne,
RL, Modugno, F, Moysich, KB, Ness, RB,
Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH,
Orlow, I, Orsulic, S, Weber, RP, Paul, J, Pearce,
CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM,
Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH,
Rudolph, A, Runnebaum, IB, Rzepecka, IK,
Salvesen, HB, Schernhammer, E, Schwaab, I, Shu,
XO, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H,
Southey, MC, Spiewankiewicz, B, Sucheston, L,
Teo, SH, Terry, KL, Thompson, PJ, Thomsen, L,
Tangen, IL, Tworoger, SS, van Altena, AM,
Vierkant, RA, Vergote, I, Walsh, CS,
Wang-Gohrke, S, Wentzensen, N, Whittemore, AS,
Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo,
YL, Yang, H, Zheng, W, Ziogas, A, Hasmad, HN,
Berchuck, A, Georgia Chenevix-Trench on behalf
of the, Amg, Iversen, ES, Schildkraut, JM, Ramus,
SJ, Goode, EL, Monteiro, AN, Gayther, SA, Narod,
SA, Pharoah, PD, Sellers, TA, Phelan, CM.
Common Genetic Variation In Cellular Transport
Genes and Epithelial Ovarian Cancer (EOC) Risk.
PLoS One, 10: e0128106, 2015. (PMID: 26091520)
J018.
Ebi, H, Oze, I, Nakagawa, T, Ito, H,
Hosono, S, Matsuda, F, Takahashi, M, Takeuchi,
S, Sakao, Y, Hida, T, Faber, AC, Tanaka, H,
Yatabe, Y, Mitsudomi, T, Yano, S, Matsuo, K.
Lack of Association between the BIM Deletion
Polymorphism and the Risk of Lung Cancer with
and without EGFR Mutations. J Thorac Oncol, 10:
59-66, 2015. (PMID: 25384174)
J019.
Fernández, E., Lugo, A., Clancy, L.,
Matsuo, K., La, Vecchia, C., Gallus, S.: Smoking
dependence in 18 European countries: Hard to
maintain the hardening hypothesis. Prev Med, 81:
314-319, 2015. (PMID: 26441299)
J017.
Darabi, H, McCue, K, Beesley, J,
Michailidou, K, Nord, S, Kar, S, Humphreys, K,
Thompson, D, Ghoussaini, M, Bolla, MK, Dennis,
J, Wang, Q, Canisius, S, Scott, CG, Apicella, C,
Hopper, JL, Southey, MC, Stone, J, Broeks, A,
Schmidt, MK, Scott, RJ, Lophatananon, A, Muir,
K, Beckmann, MW, Ekici, AB, Fasching, PA,
Heusinger, K, Dos-Santos-Silva, I, Peto, J,
Tomlinson, I, Sawyer, EJ, Burwinkel, B, Marme,
F, Guenel, P, Truong, T, Bojesen, SE, Flyger, H,
Benitez, J, Gonzalez-Neira, A, Anton-Culver, H,
Neuhausen, SL, Arndt, V, Brenner, H, Engel, C,
Meindl, A, Schmutzler, RK, German Consortium
J020.
Fernandez-Cuesta, L1., Plenker, D.,
Osada, H., Sun, R., Menon, R., Leenders, F.,
Ortiz-Cuaran, S., Peifer, M., Bos, M., Daßler, J.,
Malchers, F., Schöttle, J., Vogel, W., Dahmen, I.,
Koker, M., Ullrich, RT., Wright, GM., Russell, PA.,
Wainer, Z., Solomon, B., Brambilla, E.,
Nagy-Mignotte, H., Moro-Sibilot, D., Brambilla,
CG., Lantuejoul, S., Altmüller, J., Becker, C.,
Nürnberg, P., Heuckmann, JM., Stoelben, E.,
Petersen, I., Clement, JH., Sänger, J., Muscarella,
LA., la Torre, A., Fazio, VM., Lahortiga, I.,
Perera, T., Ogata, S., Parade, M., Brehmer, D.,
46
H, Yokoi, K, Tajima, K, Takezaki, T. Cigarette
smoke inhalation and risk of lung cancer: a
case-control study in a large Japanese population.
Eur J Cancer Prev, 2014. (PMID: 24911999)
Vingron, M., Heukamp, LC., Buettner, R., Zander,
T., Wolf, J., Perner, S., Ansén, S., Haas, SA.,
Yatabe, Y., Thomas, RK.: CD74-NRG1 fusions in
lung adenocarcinoma. Cancer Discov, 4: 415-22,
2014. (PMID: 24469108)
J027. Fukumoto, K, Ito, H, Matsuo, K, Tanaka,
H, Yokoi, K, Tajima, K, Takezaki, T. Cigarette
smoke inhalation and risk of lung cancer: a
case-control study in a large Japanese population.
Eur J Cancer Prev, 24: 195-200, 2015. (PMID:
24911999)
J021.
Fowke, JH, McLerran, DF, Gupta, PC,
He, J, Shu, XO, Ramadas, K, Tsugane, S, Inoue,
M, Tamakoshi, A, Koh, WP, Nishino, Y, Tsuji, I,
Ozasa, K, Yuan, JM, Tanaka, H, Ahn, YO, Chen,
CJ, Sugawara, Y, Yoo, KY, Ahsan, H, Pan, WH,
Pednekar, M, Gu, D, Xiang, YB, Sauvaget, C,
Sawada, N, Wang, R, Kakizaki, M, Tomata, Y,
Ohishi, W, Butler, LM, Oze, I, Kim, DH, You, SL,
Park, SK, Parvez, F, Chuang, SY, Chen, Y, Lee,
JE, Grant, E, Rolland, B, Thornquist, M, Feng, Z,
Zheng, W, Boffetta, P, Sinha, R, Kang, D, Potter,
JD. Associations of Body Mass Index, Smoking,
and Alcohol Consumption With Prostate Cancer
Mortality in the Asia Cohort Consortium. Am J
Epidemiol, 182: 381-389, 2015. (PMID: 26243736)
J028.
Gao, W., Gu, Y., Li, Z., Cai, H., Peng, Q.,
Tu, M., Kondo, Y., Shinjo, K., Zhu, Y., Zhang, J.,
Sekido, Y., Han, B., Qian, Z., Miao, Y.:
miR-615-5p is epigenetically inactivated and
functions as a tumor suppressor in pancreatic ductal
adenocarcinoma. Oncogene, 34: 1629-40, 2015.
(PMID: 24769899)
J029.
Ghoussaini,
M,
Edwards,
SL,
Michailidou, K, Nord, S, Cowper-Sal Lari, R,
Desai, K, Kar, S, Hillman, KM, Kaufmann, S,
Glubb, DM, Beesley, J, Dennis, J, Bolla, MK,
Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah,
M, Luben, R, Brown, J, Czene, K, Darabi, H,
Eriksson, M, Klevebring, D, Bojesen, SE,
Nordestgaard, BG, Nielsen, SF, Flyger, H,
Lambrechts, D, Thienpont, B, Neven, P, Wildiers,
H, Broeks, A, Van't Veer, LJ, Th Rutgers, EJ,
Couch, FJ, Olson, JE, Hallberg, E, Vachon, C,
Chang-Claude, J, Rudolph, A, Seibold, P,
Flesch-Janys, D, Peto, J, Dos-Santos-Silva, I,
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KY, Ahsan, H, Pan, WH, Qiao, YL, Gu, D,
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Parvez, F, Chuang, SY, Fan, JH, Shen, CY, Chen,
Y, Grant, EJ, Lee, JE, Sinha, R, Matsuo, K,
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Yoshida, N., Karube, K., Utsunomiya, A.,
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Yoshida, N., Tsuzuki, S., Karube, K.,
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M., Shimoyama, M., Tsukasaki, K., Ohshima, K.,
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Yusa A, Toneri T, Masuda T, Ito S,
Yamamoto S, Okochi M, Kondo N, Iwata H,
Yatabe Y, Ichinosawa Y, Kinuta S, Kondo E,
Honda H, Arai F, Nakanishi H.: Development of a
New Rapid Isolation Device for Circulating Tumor
Cells (CTCs) Using 3D Palladium Filter and Its
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Zhang, R., Liu, T.Y., Senju, S., Haruta,
M., Hirosawa, N., Suzuki, M., Tatsumi, M., Ueda,
N., Maki, H., Nakatsuka, R., Matsuoka, Y., Sasaki,
Y., Tsuzuki, S., Nakanishi, H., Araki, R., Abe, M.,
Akatsuka, Y., Sakamoto, Y., Sonoda, Y.,
Nishimura, Y., Kuzushima, K., Uemura, Y.:
Generation of mouse pluripotent stem cell-derived
proliferating myeloid cells as an unlimited source of
functional
antigen-presenting
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Zhang, Y, Su, HJ, Pan, KF, Zhang, L,
Ma, JL, Shen, L, Li, JY, Liu, WD, Oze, I, Matsuo,
K, Yuasa, Y, You, W. Methylation status of blood
leukocyte DNA and risk of gastric cancer in a
63
Oncogenesis, Springer International Publishing,
155-182, 2014.
Reviews and Books
R001. Goto, H., Kasahara, K., Inagaki, M.:
Novel insights into Chk1 regulation by
phosphorylation. Cell Struct Funct, 40: 43-50, 2015.
(PMID: 25748360)
R002. Goto, H., Inagaki, M.: Method for
generation of antibodies specific for site-and
post-translational
modifications.
Monoclonal
Antibodies, Methods and Protocols, Second Edition,
“Methods in molecular biology” series, eds.
Ossipow V. and Fischer N. Humana Press. 1131:
21-31, 2014. (PMID: 24515457)
R003. Goto, H., Inagaki, M.: New insights into
roles of intermediate filament phosphorylation and
progeria pathogenesis. IUBMB Life, 66: 195-200,
2014. (PMID: 24659572)
R004. Goto, H., Tanaka, H., Kasahara, K.,
Inagaki, M.: Phospho-specific antibody probes of
intermediate filament (IF) proteins. Intermediate
Filament Proteins, Methods in Enzymology, eds.
Omary, B., Liem, R., Elsevier. In press.
R005. Ito,
H,
Matsuo,
K.
Molecular
epidemiology, and possible real-world applications
in breast cancer. Breast Cancer, 2015. (PMID:
25862066)
R006. Murata, T., Tsurumi, T.: Switching of EBV
cycles between latent and lytic states. Rev Med
Virol, 24: 142-153, 2014. (PMID: 24339346)
R007. Oneyama, C., Okada, M.: MicroRNAs as the
fine-tuners of Src oncogenic signaling. J Biochem:
157(6), 431-438, 2015. (PMID: 25862810)
R008. Oneyama, C., Okada, Masato.: Spational
regulation of Src via lipid rafts and cancer
progression. Jikken Igaku, 33(10): 82-87, 2015.
R009. Reiji Kannagi, Keiichiro Sakuma, Bi-He
Cai, Shin-Yi Yu.: Tumor-associated glycans and
their functional roles in the multistep process of
human cancer progression. Sugar chain, 139-58,
2015. (Springer)
R010. Thirion, M., Kanda, T., Murakami, Y.,
Ochiya, T., Iizasa, H.: MicroRNAs and oncogenic
human viruses. MicroRNAs: Key Regulators of
64
Registries in Ottawa, Ottawa, 2014.
Abstracts for international conferences
A009. Kanda, T.: Roles of BART microRNAs in
EBV-infected epithelial cells. EBV 50th
anniversary, Oxford, 2014.
A001. Arita, K., Tsuzuki, S., Ohshima, K.,
Sugiyama, T., Seto, M.: Synergy of Myc, cell cycle
regulators and the Akt pathway in a mouse model
of B-cell lymphoma. American Society of
Hematology Meeting on Lymphoma Biology,
Colorado Springs, 2014.
A010. Kanda, T.: Regulation of cellular gene
expression by EBV-encoded miRNAs in epithelial
cells. 39th Annual International Herpesvirus
Workshop, Kobe, 2014.
A002. Hosono, S. Polymorphisms in DNA repair
genes are associated with endometrial cancer risk
among Japanese women. The 19th Japan-Korea
Cancer Research Workshop, Jeju Island, 2014.
A011. Kasugai, Y., Tsuzuki, S., Yoshida, N.,
Suguro, M., Takahara, T., Karube, K., Ohshima,
K., Seto, M.: HBZ, BCL-xL, Akt, and loss of
Ink4a/Arf synergistically transform primary murine
T cells and elicit adult T-cell leukemia/lymphoma
(ATL)-like disease in mice. 13th International
Conference of Malignant Lymphoma, Lugano,
2015.
A003. Inaba, H., Goto, H., Kasahara, K.,
Kumamoto, K., Yonemura, S., Inoko, A., Yamano,
S., Wanibuchi, H., He, D., Goshima, N., Kiyono,
T., Hirotsune, S., Inagaki, M.: Ndel1 suppresses
unscheduled cilia formation in proliferating cells by
regulating trichoplein-Aurora-A pathway. The 55th
Annual Meeting of the American Society for Cell
Biology, San Diego, 2015.
A012. Kuwahara, K.: The role of mammalian
TREX2 complex in sporadic breast cancers. The
3 rd Bandung International Biomolecular
Medicine Conference (BIBMC), Bandung,
Indonesia, 2014.
A004. Inagaki M.: New insights into roles of
intermediate filament (IF) phosphorylation and
progeria pathogenesis. The 13th biennial Gordon
Conference on Intermediate Filaments, West Dover,
2014.
A013. Miyama, T., Kawase, T., Kitaura, K.,
Chishaki R., Shibata M., Oshima, K., Hamana H.,
Kishi, H., Kuzushima, K., Saji, H., Suzuki, R.,
Ichinohe, T.: Comprehensive T-Cell Receptor
Repertoire Analysis Using Deep Sequencing and
Single
Cell
Cloning
Reveals
Extreme
Oligoclonality
of
Ex
Vivo
Expanded
Cytomegalovirus-Reactive Cytotoxic T-Cells. 57th
Annual Meeting and Exposition, American Society
of Hematology, Orlando, 2015.
A005. Inagaki, M.: Cancer research on the two
noteworthy issues: tetraploidy and primary cilia.
Aichi Cancer Center 50th anniversary International
Symposium, Nagoya, 2015.
A006. Ito, H. The risk prediction for esophaneal
cancer by drinking, smoking, and the
polymorphisms of ALDH2 and ADH1B. AACR
ANNUAL MEETING 2015, Philadelphia, 2015.
A014.
Mohan, R., Lei, L., Thompson, A.,
Shaw, C., Kasahara, K., Inagaki, M.,
Bargagna-Mohan, P.: Vimentin Phosphorylation
Patterns Differentiate Corneal Fibroblasts from
Myofibroblasts In Vitro and During Fibrosis.
Association in Research in Vision and
Ophthalmology (ARVO) meeting 2015, Colorado,
2015.
A007. Ito, H., Oze, I., Hosono, S., Watanabe M.,
Tanaka, H., Matsuo, K. Cumulative risks of gastric
cancer by PSCA polymorphism, Helicobacter
Pylori infection and smoking history in Japan.
American Association for Cancer Research
ANNUAL MEETING 2014, SAN DIEGO, 2014.
A015. Murakami-Tonami, Y., Kishida, S.,
Takeuchi, I., Katou, Y., Maris, J M., Ichikawa,
H., Kondo, Y., Sekido, Y., Shirahige, K.,
Murakami, H., Kadomatsu, K.: Inactivation of
SMC2 shows a Synergistic Lethal Response in
MYCN-amplified Neuroblastoma Cells. Advances
A008. Ito, H., Tanaka, H. Descriptive
epidemiology of cancer in the Japanese "oldest-old"
population. International Association of Cancer
65
A024. Suguro, M., Takahara, T., Arita, K.,
Yoshida, N., Kakiuchi, T., Kasugai, Y., Toby,
Dylan, Hocking., Takeuchi, I., Tsuzuki, S., Seto,
M.: Common Progenitor Cells Give Rise to Diffuse
Large B-Cell Lymphoma at Diagnosis and Relapse.
American Society of Hematology Meeting on
Lymphoma Biology, Colorado Springs, 2014.
In Neuroblastoma Research, Cologne, 2014.
A016. Nakagawa, H., Tamura, T., Mitsuda, Y.,
Goto, Y., Kamiya, Y., Kondo, T., Tanaka, H.,
Wakai, K., Hamajima, N. The association between
serum ferritin levels and atrophic gastritis among
Japanese adults. International Association of
Cancer Registries in Ottawa, Ottawa, 2014,.
A025. Tanaka, H. Advance in the Japanese
Multi-Institutional Collaborative Study. 7th General
Assembly and International Conference of Asian
Pacific Organization for Cancer Prevention (2014
APOCP), Taipei, 2014.
A017. Narita, Y., Murata, T., Kanda, T.,
Kimura, H., Tsurumi, T.: A conserved motif in the
Pre-N-terminal domain of Epstein-Barr virus DNA
polymerase catalytic subunit is required for the de
novo EBV genome synthesis. 39th Annual
International Herpesvirus Workshop, Kobe, 2014.
A026. Tanaka H., Goto H., Inoko A., Makihara
H.,
Izawa
I.,
and
Inagaki
M.:
Phosphorylation-deficient vimentin mutant mice
develop premature aging via aneuploidy and
cellular senescence. The 13th biennial Gordon
Conference on Intermediate Filaments, West Dover,
2014.
A018. Narita, Y., Murata, T., Kimura, H.,
Tsurumi, T.: A conserved motif in the
Pre-N-terminal domain of Epstein-Barr virus DNA
polymerase catalytic subunit is required for the de
novo EBV genome synthesis. EBV 50th
anniversary, Oxford, 2014.
A027. Tawara, I., Masuya, M., Kageyama, S.,
Nishida, T., Terakura, S., Murata, M., Fujiwara,
H., Akatsuka, Y., Ikeda, H., Miyahara, Y., Tomura,
D., Nukaya, I., Takesako, K., Emi, N., Yasukawa,
M., Katayama, N., Shiku, H.:
Adoptive
Transfer of WT1-Specific TCR Gene-Transduced
Lymphocytes in Patients with Myelodysplastic
Syndrome and Acute Myeloid Leukemia. Blood.
126:97, 2015. 57th American Society of
Hematology Annual Meeting, Orland, FL, Dec. 5,
2015.
A019. Oneyama, C.: MicroRNAs as the
fine-tuners
of
Src
oncogenic
signaling.
JARI&JSEV 7th Annual Meeting, Hiroshima,
2015.
A020. Sakura, T., Hayakawa, F., Sugiura, I.,
Imai, K., Usui, N., Fujisawa, S., Murayama, T.,
Yujiri, T., Kiyoi, H., Ohnishi, K., Miyazaki, Y.,
Ohtake, S., Kobayashi, Y., Matsuo, K.:
Effectiveness of High-Dose MTX Therapy for
Adult Ph-Negative ALL By Randomized Trial:
JALSG ALL202-O. 57th American Society of
Hematology Annual Meeting, Orlando, 2015.
A028. Urayama, Y. K., Takagi, M., Kawaguchi,
T., Matsuo, K., Tanaka, Y., Arakawa, Y.,
Hasegawa, D., Yuza, Y., Kaneko, T., Noguchi, Y.,
Taneyama, Y., Ota, S., Inukai, T., Yanagimachi,
M., Keino, D., Koike, K., Toyama, D., Nakazawa,
Y., Kurosawa, H., Nakamura, K., Moriwaki, K.,
Goto, H., Sekinaka, Y., Morita, D., Kato, M., Koh,
K., Ishida, Y., Ohara, A., Mizutani, S., Matsuda,
F., Manabe, A.: Genetic Susceptibility Loci for
Childhood Acute Lymphoblastic Leukemia Among
Japanese. 57th American Society of Hematology
Annual Meeting and Exposition, Orlando, 2015.
A021. Sekido, Y.: Hippo pathway inactivation in
malignant mesothelioma cells. International
Mesothelioma Interest Group, Cape Town, 2014.
A022. Sekido, Y.: Hippo pathway inactivation in
malignant
mesothelioma
cells.
Keystone
Symposium The Hippo Pathway: Signaling,
Development and Disease, New Mexico, 2015.
A023. Sekido, Y.: Hippo pathway dysregulation
in mesothelioma cells. 16th World Conference on
Lung Cancer, Denver, 2015.
A029. Yoshida, N., Karube, K., Utsunomiya, A.,
Tsukasaki, K., Imaizumi, Y., Taira, N., Uike, N.,
Nakamura, S., Umino, A., Suguro, M., Tsuzuki, S.,
Ohshima, K., Seto. M.,: Molecular Characterization
66
of
Chronic-Type
Adult
T-Cell
Leukemia/Lymphoma: Discovery of Molecular
Biomarkers for Acute Transformation. American
Society of Hematology Meeting on Lymphoma
Biology, Colorado Springs, 2014.
67
Record
of Seminars
___________________________________________________________
Invited Speakers
2014
Jan. 24 Maruyama, R. (Department of Molecular Biology, Sapporo Medical University): Exploring the
possible roles of quantitatively or qualitatively abnormal long ncRNAs in gastrointestinal cancer
initiation and progression.
Mar. 25 Aoki, K. (Division of Pharmacology, University of Fukui School of Medicine): Elucidating the
mechanism of negative regulation of the colon cancer stemness.
Dec. 15 Nicole A. Najor (Department of Pathology & Department of Dermatology, Northwestern University
Feinberg School of Medicine): Role of a Desmosome-COP9 signalosome complex in epidermal
differentiation.
2015
Feb. 6
Seno, H. (Department of Gastroenterology and Hepatology, Kyoto University Graduate School of
Medicine): Cell lineage analysis reveals potency of gastrointestinal cancer stem cell markers.
Mar. 17 Nishida, Y. (Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine):
Establishing the algorithm for the treatment of desmoid tumor.
Apr. 22
Matsuo, K. (Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences):
Medical research aiming at developing revolutionary cancer treatment: Multi-Omics study toward
personalized medicine.
Apr. 22
Tagawa, H. (Department of Hematology, Oncology, Nephrology, and Rheumatology, Akita
University School of Medicine): Elucidating pathophysiology of intractable hematopoietic tumors,
identification of novel therapeutic targets, and feedback to the clinic.
Apr. 22
Kotani, A. (Department of Hematology and Oncology, Tokai University School of Medicine):
Non-coding RNA as a clue to develop novel cancer medicine.
May. 19 Hirotsune, S. (Department of Genetic Disease Research, Graduate School of Medicine, Osaka City
University): Rearrangement of the microtubule network for neural cell migration.
Nov. 19 Abe, H. (Department of Chemistry, Graduate School of Science, Nagoya University): Drug
development based on nano-structured RNA technology.
Dec. 21 Watanabe, Y. (Laboratory of Chromosome Dynamics, Institute of Molecular and Cellular
Biosciences, Tokyo University): Mechanism of chromosomal instability leading to oncogenic
transformation.
Institute Speakers
2014
Jan. 10 Tanaka, K. (Molecular Oncology): Hippo pathway in mesothelioma cell lines : Elucidating
growth-inhibitory effects of AJUBA.
68
Jan. 16 Fujishita, T. (Molecular Pathology): Roles of bone marrow-derived cells in colon cancer metastasis.
Feb. 21 Yoshida, N. (Molecular Medicine): Integrated genome analysis of chronic ATL and mechanism of
their blast crisis.
Feb. 27 Tanaka, H. (Biochemistry): Roles of chromosomal instability (CIN) in cancer.
May. 15 Hosono, S. (Epidemiology and Prevention): An approach for preventing endometrial cancer using
large-scale hospital-based epidemiologic data.
Jun. 19 Iioka, H. (Oncological Pathology): Functional analysis of the cell polarity regulator Crb3 in
oncogenesis.
Oct. 27
Kakiuchi, T. (Molecular Medicine): Functional involvement of dysregulated Hippo pathway in
mesothelial carcinogenesis.
Nov. 4
Kanda, T. (Virology): Future prospects of the research on infection-associated cancer.
Nov. 6
Kuwahara, K. (Immunology): Functional abnormality of GANP in sporadic breast carcinogenesis.
2015
Feb. 19 Kasahara, K. (Biochemistry): Ubiquitin-proteasome system and primary cilia.
Mar. 6
Hakiri, S. (Molecular Oncology): Characterization of inactive mutations of BAP1 in mesothelioma
cell lines.
Mar. 26 Sakuma, K. (Molecular Pathology): Identification and characterization of HNRPLL as a novel
metastasis suppressor gene of colon cancer.
Apr. 22
Tsuzuki, S. (Molecular Medicine): Current status and future prospects of my research.
Dec. 25 Kuzushima, K. (Immunology): A review of cancer immunotherapy: from Coley's toxin to immune
checkpoints. - Messages from 2015 -
69
Record
of Symposium
____________________________________________________________________
Aichi Cancer Center 50th Anniversary International Symposium
“Cancer Drug Resistance: Mechanisms and Strategies for Its Circumvention”
Organizing Committee: Masahiro Aoki (Chairperson), Hiroji Iwata (Vice-Chairperson), Toyoaki Hida,
Tomohiro Kinoshita, Kei Muro, Yasushi Kojima, Satoyo Hosono, Kousuke
Kasahara, Yoshitaka Sekido (Advisor)
March 14, 2015, International Conference Center, Aichi Cancer Center.
Program of symposium
Opening Remarks: Taira Kinoshita (Aichi Cancer Center)
Opening Keynote Lecture
Chairperson: Masahiro Aoki (Aichi Cancer Center)
Frank McCormick (University of California, San Francisco, USA)
Targeting KRAS-induced stemness
Session 1. Cancer Heterogeneity and Drug Resistance
Chairperson: Takashi Takahashi (Nagoya University), Hiroji Iwata (Aichi Cancer Center)
Matthew J. Ellis (Baylor College of Medicine, USA)
Genome-directed therapeutics for endocrine therapy resistant ER+ breast cancer
Tatsuhiro Shibata (National Cancer Center)
Trans-ethnic landscape of hepatocellular carcinoma genomics
Tetsuya Mitsudomi (Kinki University)
Acquired resistance in targeted therapy against driver gene mutation in lung cancer
Session 2. Cancer stem cells, tumor dormancy, and drug resistance
Chairperson: Shinsuke Iida (Nagoya City University), Yoshitaka Sekido (Aichi Cancer Center)
Nick Barker (A*STAR Institute of Medical Biology, Singapore)
Lgr5+ stem cells in epithelial self-renewal and cancer of the stomach and ovary
Hideyuki Saya (Keio University)
Regulation of cell differentiation by actin dynamics and its application in cancer treatment
Masaki Inagaki (Aichi Cancer Center)
Cancer research on the two noteworthy issues: tetraploidy and primary cilia
Session 3. Strategies for circumvention of cancer drug resistance
Chairperson: Yutaka Kondo (Nagoya City University), Toyoaki Hida (Aichi Cancer Center)
Gianpietro Dotti (Baylor College of Medicine, USA)
T-cell therapy for cancer using gene modified T cells and strategies to overcome tumor escape or
immunosuppression
Masaaki Komatsu（Niigata University）
Loss of autophagy causes metabolic changes through a transcription-factor pathway
Yasuaki Arai (National Cancer Center Hospital)
Interventional radiology in oncology
Closing Keynote Lecture
Chairperson: Tomohiro Kinoshita (Aichi Cancer Center)
Shigekazu Nagata (Kyoto University)
Apoptosis and exposure of phosphatidylserine
Closing Remarks: Masahiro Aoki (Aichi Cancer Center)
70
Abstracts
Targeting KRAS-induced stemness
understanding of interactions between mutation
status, the prognosis of ER+ breast cancer, and the
effectiveness of endocrine therapy; 3) an inadequate
collection of patient-derived xenograft (PDX)
models for luminal breast cancer that fully
encompass the heterogeneity of the disease; 4) the
logistical barriers of developing adjuvant strategies
to exploit rare drivers present in less than 5% of
tumor samples; 5) insufficient genomic discovery
efforts directed towards samples accrued from
patients suffering from endocrine therapy resistant
disease progression and 6) an incomplete
understanding of how complex somatic genotypes
drive the biochemical events responsible for the
“hallmarks” of luminal cancer.
To better address these issues, five areas of
investigation will be discussed: 1) somatic mutation
diagnosis in DNA from primary breast cancer
samples from patients treated with adjuvant
tamoxifen and followed for over 20 years; 2) DNA
and RNA sequencing of samples accrued from
patients treated with neoadjuvant endocrine therapy
to define the molecular origins of intrinsic
aromatase inhibitor resistance and to identify
pharmacological hypothesis; 3) efforts to expand
and catalog patient-derived xenografts from ER+
breast cancers, including the use of mass
spectrometry-based analysis of their proteomes and
phosphoproteomes to expand our knowledge of the
biochemistry of individual tumors; 4) a functional
and pharmacological investigation of mutations in
ESR1, including resistance-activating chromosomal
translocations, and 5) the development of a
neoadjuvant endocrine therapy strategy that
identifies patients with intrinsic endocrine therapy
resistance within a month of starting treatment so
that they can be triaged to mutation-matched
investigational treatment.
Frank McCormick and Man-Tzu Wang
University of California, San Francisco - Helen Diller
Family Comprehensive Cancer Center, USA
Of the three Ras genes, KRAS, NRAS and
HRAS, KRAS is by far the major contributor to
human cancer, whereas HRAS is rarely activated.
In spite of this dramatic difference, KRAS and
HRAS interact with the same effectors and are
equally potent at transforming cells in culture.
However, cells transformed by KRAS have unique
properties relative to HRAS: they cause a stem-like
phenotype that enables them to grow as spheres in
culture, to establish tumors in mice at high
efficiency and to resist the effects of multiple
chemotherapy and targeted drugs. These effects are
due to KRAS’ ability to bind calmodulin, and to
inhibit calmodulin-dependent kinase. Low CaM
kinase promotes wnt signaling and initiates a set of
programs that confer stemness. Binding of K-Ras to
calmodulin is prevented by phosphorylation of
K-Ras on serine-181, by protein kinase C.
Treatment of mice with a natural product, prostratin,
that activates PKC and K-Ras phosphorylation
prevents initiation of pancreatic tumors in xenograft
models. Part of the “stemness” program initiated by
K-Ras involves secretion of the cytokine LIF, an
IL-6 family member with a unique role in
maintaining stemness. Neutralization of LIF with a
monoclonal antibody reduces stemness and
sensitizes established pancreas tumors to
gemcitabine. We propose that attacking targets in
these stem-like pathways offers new opportunities
for therapeutic intervention in KRAS-driven
cancers.
Genome-directed
therapeutics
for
endocrine therapy resistant ER+ breast
cancer
Matthew J. Ellis
Lester and Sue Smith Breast Center, Baylor College of
Medicine, USA
Trans-ethnic landscape of hepatocellular
carcinoma genomics
Tatsuhiro Shibata1,2, David A. Wheeler3, and Hiroyuki
Aburatani4
1
Division of Cancer Genomics, National Cancer Center;
2
Laboratory of Molecular Medicine, The Institute of
Medical Science; 3Human Genome Sequencing Center,
Baylor College of Medicine, USA; 4Genome Science
Division, Research Center for Advanced Science and
Technology, The University of Tokyo
As a result of improvements in DNA and RNA
sequencing techniques the genomic structure of
estrogen receptor positive breast cancer is
increasingly well documented, but extracting
clinically actionable information from these
complex data sets has proved fraught with
difficulties. Barriers to progress include the lack of
pharmacological hypotheses for novel luminal
breast cancer tumor suppressor genes (e.g.
MAP3K1, MLL3, SF3B1); 2) a lack of a full
Multiple etiological factors (hepatitis virus
infection, alcohol, obesity etc) are associated with
the occurrence of hepatocellular carcinoma (HCC)
and their contributions diverse among ethnicity. To
71
1) target gene alterations (T790M mutation in
EGFR-TKI or L1196M and other mutations in ALK,
2) activation of additional kinases (e.g., MET,
HER2 for EGFR, and KIT, EGFR, SRC for ALK)
bypassing the inhibition of the original kinases, and
3)
other
mechanisms
including
epithelial-mesenchymal transition, small cell lung
cancer transformation, etc.
To overcome T790M gatekeeper mutations,
so-called third generation EGFR inhibitors that
selectively inhibit EGFR-T790M while sparing the
wild-type EGFR are being actively developed.
Likewise, ALK-TKIs of a newer generation are
active at least for some of the secondary mutations
found in crizotinib-resistant tumors. Tumor
resistance caused by the bypass track can be coped
with by combination of the inhibitors for the
original kinase and the bypassing kinases.
However, even with these strategies, cancer
cells are smart enough to escape from the therapy
using other mechanisms. Heterogeneities in terms
of resistant mechanisms within a single patient
become evident when specific therapeutic pressure
persists. Therefore, we also need to have
armamentarium that utilizes other mechanisms to
cure lung cancer. Recent advances of
immunotherapy targeting PD-1/PD-L1 appear
attractive in this respect. These mechanism-driven
therapeutic approaches will convert this fatal
disease into a more chronic disorder, and eventually
into a curable disease with the least patient burdens.
elucidate genetic diversities in HCC genomes with
regards to ethnic and epidemiological differences,
we have conducted the trans-ethnic cancer genome
research under the umbrella of the International
Cancer Genome Consortium (ICGC) and The
Cancer Genome Atlas (TCGA).
We performed whole exome sequencing of 514
pairs of HCC, which include different ethnic
populations (424 cases from the Japanese cohort
and 90 from the US cohort) with various etiological
backgrounds. Furthermore, whole exome data of
105 HCC cases from TCGA was included in the
mutation signature analysis. Mutation call
algorithms of three collaborating genome centers
(National Cancer Center, Tokyo, Research Center
for Advanced Science and Technology in the
University of Tokyo, and Baylor College of
Medicine, Houston) were adjusted and validated by
the Ion Proton sequencer. In total, more than
100,000 somatic mutations were collected, and their
signatures were significantly associated with
ethnicity and gender, but not with the hepatitis virus
status. In addition to TP53, WNT, and SWI/SNF
pathways, aberrant activation of the TERT pathway
by various mechanisms (promoter/coding mutations,
gene amplification and viral genome integration)
was found to play a central role in
hepatocarcinogenesis. Aggregation of the large
cancer genome data by ICGC and TCGA has
rapidly progressed. In addition to the cross-tumor
analysis (Pan-Cancer study), population-based
meta-cancer genome analysis would provide us
unique and diverse landscapes of the cancer
genomes on this planet.
Lgr5+ stem cells in epithelial self-renewal
and cancer of the stomach and ovary
Nick Barker, Marc Leushacke, Annie Ng
A-STAR* Institute of Medical Biology, Singapore
Acquired resistance in targeted therapy
against driver gene mutation in lung cancer
1
1
The availability of robust cell-surface markers for
identifying and isolating adult stem cells is essential
for studying both their normal in-vivo function
during tissue renewal and for evaluating their
contribution to cancer. Lgr5, a Wnt target gene
expressing a 7-TM receptor that functions as
facultative component of the Wnt receptor complex,
has been shown to selectively mark stem cells in a
range of rapidly renewing tissues, including the
small intestine, colon, stomach, hair follicle and
developing kidney. Clonal fate mapping employing
the stem cell-specific Lgr5-CreERT2 line has been
used to further dissect how these adult stem cell
pools maintain tissue homeostasis and contribute to
tissue repair following damage. Additionally,
targeted in-vivo mutation of the Lgr5+ve adult stem
cell pools using the same Lgr5-CreERT2 model has
been used to determine the contribution of stem
cells to tumor initiation and progression in various
1
Tetsuya Mitsudomi , Kenichi Suda , Hiroshi Mizuuchi ,
Yoshihisa Kobayashi1, Kazuto Nishio2, and Yasushi
Yatabe3
Department of Thoracic Surgery1 and Genome Biology2,
Kinki Unversity Faculty of Medicine; 3Department of
Pathology and Moleclular Diagnostics, Aichi Cancer
Center Hospital
Discovery of activating mutation of the EGFR
gene in adenocarcinoma of the lung in 2004 opened
the era of personalized therapy in thoracic oncology.
These tumors are highly dependent on the EGFR
pathway and EGFR-tyrosine kinase inhibitors (TKI)
significantly prolong progression free survival in
these patients compared with chemotherapy. In
2007, EML4-ALK translocation was found and
these tumors are very sensitive to ALK-TKI.
However, acquired resistance inevitably develops
usually after a median of 10 months. The
mechanisms for this resistance can be classified into
72
vimentin with mitotic phosphorylation-defective
mutations to impair cytokinesis. Homozygotic
(VIMSA/SA) mice presented with microophthalmia
and cataracts, in which lens epithelial cells
exhibited binucleation and aneuploidy, along with
premature aging. We further analyzed the ability to
repair wounds in the skin of VIMSA/SA mice, and
found that some subcutaneous tetraploid fibroblasts
caused by cytokinetic failure enter a new cell cycle
and then develop into aneuploid fibroblasts in vivo,
which promotes premature aging. We suggest that
tetraploidy without the genetic alteration of
cancer-related genes may be associated with
premature aging rather than carcinogenesis.
Non-motile primary cilia are microtubule-based
sensory organelles that regulate a number of
signaling pathways during development and tissue
homeostasis. Tumor cells are known to often lack
primary cilia, but whether their loss is directly
linked to tumorigenesis is completely unclear. We
have recently found that ubiquitin-proteasome
machinery removes trichoplein, a negative regulator
of ciliogenesis, from mother centrioles and thereby
causes Aurora-A inactivation, leading to
ciliogenesis. We have identified KCTD17 as a
substrate-adaptor for Cul3-RING E3 ligases
(CRL3s) that polyubiquitylates trichoplein.
Depletion of KCTD17 specifically arrests
ciliogenesis at the initial step of axoneme (ciliary
microtubule doublet) extension through aberrant
trichoplein-Aurora-A activity. We would like to
discuss the relationship between primary cilia and
cancer stem cells, which may be implicated in drug
resistance against cancer chemotherapy.
epithelia. A summary of the latest findings in the
stomach and ovary will be presented here.
Regulation of cell differentiation by actin
dynamics and its application in cancer
treatment
Hideyuki Saya and Hiroyuki Nobuse
Division of Gene Regulation, Institute for Advanced
Medical Research, School of Medicine, Keio University
Differentiation status is strongly associated with the
behavior of cancer cells. Therefore, changes in the
cellular context, which regulates the differentiation
potential, may serve in novel therapeutic strategies
in treating cancers.
We have established a mouse osteosarcoma (OS)
model through overexpression of c-MYC in bone
marrow stromal cells (BMSCs) derived from
Ink4a/Arf (-/-) mice. In this model, we found that
the loss of adipogenic potential was an essential
event for OS development. Therefore, our
understanding of regulatory mechanisms of
adipocyte differentiation would greatly contribute
to control OS tumorigenesis.
Adipocytic differentiation is accompanied by the
adoption of a rounded cell shape that is
characteristic of mature adipocytes. Cell shape is
determined primarily by the actin cytoskeleton. We
have recently found a novel regulatory mechanism
of adipocyte differentiation, in which regulation of
transcriptional coactivator MKL1 by actin
cytoskelton
dynamics
drives
adipocyte
differentiation mediated by PPARγ, a master
transcriptional
regulator
of
adipogenesis.
Accordingly, adipocyte differentiation can be
induced by the disruption of actin stress fibers
through down-regulation of RhoA-ROCK signaling.
Based on this concept, we attempted to induce
adipocyte differentiation in OS cells, which resulted
in a significant suppression of tumorigenesis.
Induction of trans-differentiation in cancer stem
cells by regulating actin cytoskeleton dynamics is a
potential approach for some tumor types.
T-cell therapy for cancer using gene
modified T cells and strategies to overcome
tumor escape or immunosuppression
Gianpietro Dotti
Center for Cell and Gene Therapy, Baylor Colledge of
Medicine, USA
T-lymphocyte-based treatments have enormous
potential in cancer patients. Over the past decade, T
cells mo dified to express chimeric antigen
receptors (CARs) have had clinical success in
B-lymphocyte derived malignancies. In the specific
context of CAR-T cells therapies for B-cell
malignancies we developed at Baylor a strategy
aimed at achieving antitumor effects, but limiting
the prolonged B-cell aplasia caused the infusion of
CD19-CAR-specific T cells. We are currently
targeting
the
k-light
chain
of
human
immunoglobulins expressed on the cell surface of
k+lymphoma cells in an effort to target lymphomas
cells but spare normal l+B-lymphocytes. An update
Cancer research on the two noteworthy
issues: tetraploidy and primary cilia
Masaki Inagaki
Division of Biochemistry, Aichi Cancer Center Research
Institute and Department of Cellular Oncology, Nagoya
Tetraploidy, a state in which cells have doubled
chromosomal sets, is observed in ~20% solid
tumors and considered to frequently precede
aneuploidy in carcinogenesis. Tetraploidy is also
detected during tissue differentiation and aging
process. We generated knock-in mice featuring
73
image guidance.
There are two routes to access to the target
lesion; trans-canal and direct puncture. The typical
type of trans-canal approach is transarterial
chemoembolization (TACE) for hepatocellular
carcinoma (HCC), in which the feeding arteries are
occluded with anticancer drug to kill tumor cells
with stasis of blood flow. TACE could obtain total
necrosis if the HCC tumor is hyper-vascular and
less than 5cm in diameter. In a decade,
microspheres with drug eluting and Yttrium-90
have been developed to treat HCCs with various
stages. The other approach with percutaneous direct
puncture is thermal ablation, such as radiofrequency
ablation (RFA), microwave ablation, cryoablation
for tumors in the liver, kidney, lung, etc. TACE and
RFA are established as the standard treatment for
early and intermediate stage HCC.
Moreover, there are novel IR treatments;
high-intensity focused ultrasounds (HIFU) and
irreversible electroporation (IRE). HIFU kills tumor
cells with thermal ablation by high-intensity
focused ultrasounds without needle puncture. IRE
kills tumor cells with membrane with
electroporation by high voltage pulse without the
destruction of anatomical structures.
IR can be complementary with other treatment
modalities because the mechanism of anti-tumor
effect in IR is completely different from that of
medical and radiation therapy.
On the other hand, IR is difficult to establish
evidence by clinical trials, because the clinical
results in IR greatly depend on the operator’s skills
and equipment. We started to conduct many
multi-institutional clinical trials in Japan more
earlier than western countries, however, still it is
very challenging for us to establish IR as one of the
standard treatments in the oncology field.
of the clinical trial currently ongoing will be
presented.
In contrast to B-cell malignancies, the clinical
efficacy of CAR-T cells remains limited in solid
tumors. This unfavorable outcome could be due to
the insufficient migration of the infused T cells to
the tumor site and to the immunosuppressive
characteristics of the tumor environment, which
inhibit the effector function and proliferation of
those few T cells that do reach the tumor. We
recently found that tumor-specific engineered T
lymphocytes expanded ex vivo for adoptive T-cell
therapy are defective in their capacity to degrade
one critical component of the extracellular matrix.
We also found that this defect can be however
repaired by the ectopic expression of the enzyme
heparanase. We also found that armed oncolytic
viruses expressing RANTES and IL-15 can be used
to favor the migration of CAR-T cells at the tumor
site and promote the survival of CAR-T cells within
the hostile tumor environment.
Loss of autophagy
changes through a
pathway
causes metabolic
transcription-factor
Masaaki Komatsu
Department of Biochemistry, School of Medicine, Niigata
University
Autophagy provides starved cells with amino
acids, free fatty acids, and glucose for new protein
synthesis energy production; autophagy also
controls the quality and quantity of organelles such
as mitochondria. Therefore, it is plausible that
autophagy might be integrated with metabolic
pathways. Indeed, suppression of autophagy causes
myopathy, tumorigenesis, and metabolic disorders
in mice and humans. However, the metabolic
changes associated with deficiencies in autophagy
are largely unknown. Furthermore, it remains
unclear whether the major predisposing factor for
the aforementioned diseases in the absence of
normal autophagic activity is a simple deficit in
supply of molecular building blocks, dysregulation
of mitochondrial homeostasis, or some other cause.
Here, we show that deficiencies in autophagy are
associated with rearrangement of glucose and
glutamine metabolism via a transcriptional
regulatory mechanism.
Apoptosis
and
phosphatidylserine
exposure
of
Shigekazu Nagata
Department of Medical Chemistry, Graduate School of
Apoptotic cells are swiftly engulfed by
macrophages. If this process does not occur
properly, materials released from dead cells activate
the immune system, leading to systemic lupus
erythematosus-type
autoimmune
disease.
Phospholipids in plasma membranes are
asymmetrically distributed between inner and outer
leaflets, and phosphatidylserine (PtdSer) is
exclusively localized in the inner leaflet. The
asymmetrical distribution of phospholipids is
maintained by an ATP-dependent phospholipid
Interventional radiology in oncology
Yasuaki Arai
National Cancer Center Hospital
IR is a minimally invasive treatment modality in
which small devices are percutaneously inserted
into a patient’s body with minimum incision under
74
8 transmembrane regions, requires Ca2+ to support
phospholipid scrambling, and plays an essential role
in the PtdSer-exposure in activated platelets. Xkr8
is a protein carrying 6 transmembrane regions, and
caspases cleave off its C-terminal tail to promote
the scramblase activity. ATP11C is a P4-type
ATPase at plasma membrane, and CDC50A works
as a chaperone to transport ATO11C from
endoplasmic reticulum to plasma membranes.
ATP11C translocates PtdSer from outer to inner
leaflets of plasma membranes in an ATP-dependent
manner. When cells undergo apoptosis, ATP11C is
inactivated
by
caspase-mediated
cleavage,
indicating that in addition to the caspase-mediated
activation of scramblase, inactivation of flippase is
required to expose PtdSer during apoptosis.
Lymphoma cells that lack the flippase
constitutively expose PtdSer, are engulfed by
macrophages, and can not develop tumors in nude
mice. These results indicate that PtdSer is necessary
and sufficient as an “eat me” signal to be
recognized
by
macrophages,
and
the
PtdSer-expressing tumor cells can be killed by
being engulfed by macrophages.
translocase or flippase. When cells undergo
apoptosis, or platelets are activated, the
asymmetrical distribution of phospholipids is
disrupted
by
scramblase,
leading
to
PtdSer-exposure. The PtdSer exposed on dead cell
surface is recognized by macrophages as an “eat
me” signal, while PtdSer on activated platelets
provides the scaffold for clotting factors. We
recently identified two membrane proteins
(TMEM16F and Xkr8) as phospholipid scramblases,
and a pair of membrane proteins (ATP11C and
CDC50A) as a flippase. TMEM16F, a protein with
75
76

2014-2015

Transcription

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