Migrating cancer stem cells — an integrated concept of malignant

Transcription

PERSPECTIVES
OPINION
Migrating cancer stem cells — an
integrated concept of malignant
tumour progression
Thomas Brabletz, Andreas Jung, Simone Spaderna, Falk Hlubek and
Thomas Kirchner
Abstract | The dissemination of tumour
cells is the prerequisite of metastases
and is correlated with a loss of epithelial
differentiation and the acquisition of a
migratory phenotype, a hallmark of malignant
tumour progression. A stepwise, irreversible
accumulation of genetic alterations is
considered to be the responsible driving
force. But strikingly, metastases of most
carcinomas recapitulate the organization
of their primary tumours. Although current
models explain distinct and important
aspects of carcinogenesis, each alone can
not explain the sum of the cellular changes
apparent in human cancer progression.
We suggest an extended, integrated model
that is consistent with all aspects of human
tumour progression — the ‘migrating cancer
stem (MCS)-cell’ concept.
Carcinomas, which represent the most
prevalent malignancies in humans, arise
from normal epithelial tissues in a multistep
progression from benign precursor lesions.
Metastasis — the final step in malignancy —
is the main cause of death for cancer patients.
Recent models explain selected aspects of the
complex tumour-progression process: for
example, unrestricted growth, a hallmark of
both benign and malignant tumours, can be
attributed to cancer stem cells1. Generally,
a stepwise accumulation of genetic alterations in oncogenes and tumour-suppressor
genes is considered to be a driving force for
malignancy. The breakdown of epithelial-cell
homeostasis leading to aggressive cancer
progression is correlated with the loss of epithelial characteristics and the acquisition of
a migratory phenotype. This phenomenon,
referred to as the epithelial to mesenchymal
transition (EMT), is considered to be a crucial
event in malignancy2.
The important steps that enable metastasis are reversible, and therefore cannot
be explained solely by irreversible genetic
alterations3, indicating the existance of a
744 | SEPTEMBER 2005
dynamic component to human tumour
progression4. In particular, a regulatory role
for the tumour environment has already
been demonstrated in many experimental
systems5. Tumours do not act as autonomous proliferation machines, but are very
heterogeneous, both in their morphological and functional aspects. In fact, an individual tumour shows distinct sub-areas of
proliferation and cell-cycle arrest, epithelial
differentiation and EMT, cell adhesion and
dissemination. How are all these different
traits orchestrated? Based on our observations in human colorectal cancer, we suggest
an extended, integrated model that covers all
aspects of human tumour progression — the
‘migrating cancer stem (MCS)-cell’ concept.
Colorectal cancer as a model tumour
Human colorectal cancer is one of the
most extensively investigated tumour
types, for which many of the steps from
small low-grade adenomas to metastatic
carcinomas are clearly defined. Almost all
cases show aberrant activation of the Wnt
pathway, mostly due to loss-of-function
mutations in the adenomatous polyposis
coli (APC) tumour-suppressor gene6. One
hallmark of Wnt-pathway activation is the
nuclear accumulation of its main effector
β-catenin, which is one component of a
transcriptional activation complex that
includes members of the TCF/LEF family
of DNA binding proteins7. The evolutionarily conserved Wnt signalling pathway has
pivotal roles during the development of
many organ systems, and its dysregulation
is a key factor for the initiation of various
tumours. Importantly, Wnt signalling is
involved in both stem-cell formation and
the induction of EMT.
Physiologically, stem cells give rise to all
tissues during embryonic development and
are also the basis for tissue homeostasis in the
adult organism8. The hallmark of stem cells
is their capacity for asymmetric division,
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resulting in both self renewal of the stem cell
and the subsequent proliferation and differentiation of the second daughter cell. Wnt signalling is involved in the generation of embryonic
stem cells9,10, tissue stem cells and also in adult
tissue homeostasis. Examples are development of the intestine11,12, hair follicles13,14
and haematopoiesis15. In particular, correct
intestinal development was shown to depend
on a functional Wnt pathway — depletion of
transcription factor 4 (TCF4), a gut-specific
member of the Tcf family, resulted in a lack of
epithelial stem cells in the intestine11.
EMT and the reverse transition from
a mesenchymal to an epithelial phenotype (MET) are fundamental processes of
embryonic development. Wnt signalling
is involved in the induction of EMT in
physiological processes such as gastrulation 16 and the development of the heart
cushion17, and when it is aberrantly activated, Wnt also induces EMT in tumour
cells18–21. An important hallmark of EMT
is the loss of membranous E-cadherin
in adherens junctions, which is indicative of one of the molecular mechanisms
through which β-catenin might participate in EMT. Translocation of β-catenin
from adherens junctions to the nucleus
might trigger the loss of E-cadherin and,
subsequently, the EMT. Moreover, nuclear
β-catenin can directly transcriptionally
activate EMT-associated target genes, such
as the E-cadherin gene repressor SLUG
(also known as SNAI2) 22 . Accordingly,
these functions can explain the oncogenic potency of the Wnt pathway (and
β-catenin) when it is aberrantly activated
during carcinogenesis. So the Wnt pathway
links two important components of tumour
progression: the existence of cancer stem
cells and the initiation of EMT.
The notion of cancer stem cells was initially proposed to explain some of the key
findings in leukaemia research23 and it has
been successfully adapted to explain the
behaviour of solid tumours24 . Mutations
in crucial signalling pathways, such as the
Notch, Wnt and Hedgehog pathways, might
cause normal stem cells to become independant of regulatory signals that are generated
by their normal environmental niche. So,
the resulting mutated stem cells have already
taken one initial step towards the evolution
of benign precursor lesions1,25,26. The three
characteristics attributed to stem cells — self
renewal, extensive proliferation and differentiation capacity — can explain both the
unrestricted growth and the differentiated
growth patterns that are detectable in both
benign and malignant tumours.
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© 2005 Nature Publishing Group
PERSPECTIVES
One prerequisite for metastasis is the
dissemination of tumour cells through
blood and lymphatic vessels, which can be
strongly enhanced by EMT 27 . However,
many primary epithelial tumours grow in
differentiated, epithelial patterns and recapitulate the basic morphology of the original
tissue, without evidence of EMT in the main
tumour mass. Nevertheless, such tumours
can and do metastasize. In these tumours, a
loss of differentiation, similar to an EMT, is
often detectable at the tumour–host interface
and is thought to enable cellular detachment,
dissemination and finally metastasis28,29. Like
‘stemness’, EMT is regulated by fundamental embryonic pathways such as the Wnt
pathway and transforming growth factor β
(TGFβ) pathway, both of which are often
aberrantly activated in cancer30.
Both the EMT concept and the cancer
stem-cell concept cover distinct aspects of
carcinogenesis; however, each alone cannot
explain all of the cellular changes evident
during the evolution of metastatic lesions.
Primary carcinoma
Liver metastasis
Wnt activation at the invasive front
Nuclear β-catenin, the presence of which
indicates an active Wnt pathway, can be
detected in colorectal tumours. However,
the intracellular localization of oncogenic
β-catenin is very heterogenous in tumour
cells and reflects the heterogeneity of tumourcell differentiation, both within an individual
tumour and in different phases of progression between adenoma to carcinoma3,31,32. In
stained colorectal cancer tissue sections, the
strongest accumulation of nuclear β-catenin
is found predominantly in dissociated,
dedifferentiated tumour cells that are at the
tumour–host interface, that have undergone
EMT (FIG. 1), that have lost expression of
E-cadherin and that are growth arrested as
a result of increased expression of the cellcycle dependent kinase inhibitor INK4a (also
known as CDKN2A and p16)33. In most cases
of typically well to moderately differentiated
colorectal carcinomas, a gradual loss of
nuclear β-catenin is seen towards central,
well-differentiated (epithelial-like) areas of
the tumour. In addition to the spatial heterogeneity within an individual tumour, there is
a temporal heterogeneity. During the progression from adenoma to carcinoma, there is an
increase in nuclear β-catenin, starting with
small quantities in a few areas in low-grade
adenomas and reaching a maximum in EMTassociated tumour cells at the tumour–host
interface in carcinomas31. Strikingly, the EMT
process must be reversible, as most metastases re-express E-cadherin, have reduced
expression of nuclear β-catenin and thereby
Dedifferentiated tumour cells with
strong nuclear β-catenin expression
Direction of differentiation
Differentiated tumour areas
Figure 1 | Phenotype and β-catenin expression pattern in colorectal cancer (primary carcinoma)
and liver metastasis. Nuclear β-catenin (brown staining) accumulates in dedifferentiated tumour cells at
the tumour–host interface that have undergone epithelial to mesenchymal transition (EMT) (thin arrows).
Towards central tumour areas (thick arrows), tumour cells differentiate and polarize, building up tubular
structures and loose nuclear β-catenin staining. It is worth noting that this heterogenous pattern of the
primary tumour is recapitulated in corresponding metastases, for example in the liver. The inserts show
magnifications of the corresponding central and invasive areas. Below each image are schematic
drawings that indicate EMT and concentric differentiation.
recapitulate the differentiated phenotype of
their primary tumours. Moreover, the same
heterogenous pattern, both in tumour-cell
phenotype (the degree of central differentiation and peripheral EMT) and intracellular
β-catenin distribution is again detectable in
corresponding metastases3,34 (FIG. 1). So, we
have suggested that the EMT in disseminating
tumour cells is only transient and is reversed
by a MET in established metastases3,4.
Do these observations give any hints as
to the molecular mechanisms and regulatory forces responsible for the complex
morphological and functional changes
(differentiation versus EMT, proliferation
NATURE REVIEWS | C ANCER
versus cell-cycle arrest and cellular adhesion
versus dissemination) within an individual
tumour during tumour progression?
All of these features are detectable in
many human cancers and we are convinced
that these observations provide basic clues for
further understanding tumour progression.
The increasing number of identified Wnt/βcatenin target genes that are overexpressed in
tumours also give decisive hints. Consistent
with its role in development, many β-catenin
target genes are involved in promoting stemness (for example, survivin (also known as
baculoviral inhibitor of apoptosis (IAP)
repeat-containing protein 5, BIRC5)) and
VOLUME 5 | SEPTEMBER 2005 | 745
PERSPECTIVES
Normal mucosa
Adenoma
Carcinoma
Liver metastasis
β-catenin
Survivin
L1CAM
Figure 2 | Expression of stem cell- and EMT-markers in colorectal cancer progression. The
images show serial histological sections for each progression step with specific protein staining shown in
brown. Stem-cell-associated Wnt target genes, such as survivin, are expressed only in the basic region of
normal colonic crypts (thin arrow in left panel of images), but are distributed throughout all areas of benign
adenomas, carcinomas and metastasis, including differentiated (thick arrows) and dedifferentiated (thin
arrows) tumour cells. In contrast, epithelial to mesenchymal transition (EMT)-associated Wnt targets (such
as L1CAM and LAMC2) are not expressed in normal mucosa, adenomas and differentiated tumour areas
(thick arrows). Expression is mainly seen in disseminated tumour cells that have highest nuclear β-catenin
at the tumour host interface (thin arrows), most of which retain expression of stem cell markers. L1CAM,
L1 cell adhesion molecule; LAMC2, γ2 chain of laminin.
subsequently promoting proliferation
in transit amplifying units (for example,
c-MYC35 and CCND1 REFS 36,37). Survivin
is a bifunctional regulator that couples cell
proliferation with resistance to apoptosis.
It is only expressed in stem-cell regions of
normal tissues, but is overexpressed in many
cancers. Stimulation of survivin expression
by β-catenin might impose a stem-cell
phenotype in tumour cells in colorectal
cancer38,39. However, a second group of Wnt
targets is linked to EMT-associated processes: SLUG is a transcriptional repressor
of the gene that encodes E-cadherin22. L1
cell adhesion molecule (L1CAM)40, an axon
guidance molecule, and the isolated γ2 chain
of laminin (LAMC2)41 are strong inducers of
epithelial-cell migration.
Strikingly, the expression of Wnt targets
within the adenoma–carcinoma progression
follows a distinct sequence that is associated
with their predominant functions (FIG. 2):
stemness-associated and proliferation-
associated genes are activated very early in
carcinogenesis (for example in low-grade
adenomas) and remain expressed throughout
tumour progression. However, EMT-associated target genes show different expression
kinetics. Genes that are linked with EMT,
such as L1CAM or LAMC2, are transiently
upregulated mainly in dissociated tumour
cells that express high levels of nuclear
β-catenin. These genes are downregulated in
differentiated tumour cells in both carcinomas and metastases after a MET-like process. It is worth noting that such tumour cells,
mainly at the tumour–host interface, not only
express EMT-associated genes, but also maintain expression of stemness-associated genes,
which might have important consequences
(see below). Therefore we can group Wnt target genes into a stemness/proliferation group
that is activated early and throughout all
progression steps, and a EMT/dissemination
group that is expressed later and transiently,
mainly at the tumour–host interface (FIG. 3).
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A new concept: MCS-cells
This dynamic two-phase expression pattern
logically leads to a concept based on the
existence of two forms of cancer stem cells
in tumour progression — stationary cancer
stem cells and mobile cancer stem cells.
Stationary cancer stem cells (SCS cells),
which are still embedded in the epithelial
tissue, are already active in benign precursor
lesions, such as adenomas, and persist in differentiated areas throughout all the steps of
tumour progression (corresponding to phase
I in FIG. 3); however the SCS cells cannot
disseminate. The term ‘mobile cancer stem
cells’ describes stem cells that are located predominantly at the tumour–host interface, and
which are derived from SCS-cells through the
acquisition of a transient EMT in addition to
stemness (corresponding to phase II in FIG. 3).
A tumour cell, which combines the two perhaps most decisive traits, stemness and mobility (traits that are not normally combined in
a single epithelial cell) hold important clues
for the further understanding of malignant
progression. We call these cells ‘migrating
cancer stem (MCS)-cells’, and these take into
account two important requirements — cancer stem cells that have undergone EMT can
disseminate, and disseminating cancer cells
that retain stem-cell functionality can form
metastatic colonies. In colorectal cancer we
have characterised potential MCS cells as
the cells that express high levels of nuclear
β-catenin. It is worth noting that the number
of isolated tumour cells that express high levels of nuclear β-catenin at the tumour–host
interface — which we consider to be MCS
cells — is strongly correlated with metastasis
and poor survival (REFS 42,43 and T.B., A.J.,
S.S., F.H. and T.K. unpublished observations).
The MCS-cell concept (FIG. 4) has immediate
consequences, particularly for how malignant
tumours grow and metastasize. Moreover, the
MCS-cell concept integrates the important
current tumour initiation and progression
concepts: the cancer stem cell and EMT
concept, as well as accumulation of genetic
alterations and the tumour environment as
responsible driving forces.
How can the differential activation
of the stem cell and the EMT-program
be explained at the molecular level? It is
important to take into account that the
stem-cell programme needs to be physiologically active in normal colon mucosa
to maintain homeostasis (as it is in all
stem-cell niches in adult tissues), but is
restricted to the basal crypt regions. In
contrast, the EMT-program is normally
not active in adult colon mucosa (or in
other adult epithelial tissues); therefore,
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Phase
Wnt-targets
II
L1CAM
Laminin γ2
MMP14
ET
M
APC or β-catenin mutation:
low nuclear β-catenin
Stem cell phenotype
+ dissemination
EM
T
+ Environmental signals:
increasing nuclear β-catenin
Survivin
I
Stem cell phenotype and growth
Normal
mucosa
Adenoma
Cyclin D
MYC
Survivin
Carcinoma or metastasis
Figure 3 | Schematic of dynamic tumour progression. The data deduced from expression analyses of
human tumours are summarized as a two-phase model. Inappropriate activation of ‘stemness’ in selected
tumour cells and subsequent proliferation and epithelial differentiation in the main tumour mass can be
detected in all steps from early adenomas to metastases (phase I). So, low quantities of β-catenin might
be sufficient for the persistant activation of stemness in all steps of tumour progression. Tumour cells are
attached to each other in an epithelial context. The activation of phase II (possibly by aberrant
environmental signals) in both primary carcinomas and metastases is the hallmark of malignancy and
enables dissemination. The cyclical dynamics of this model are indicated by the transient expression of
epithelial to mesenchymal transition (EMT)-associated genes, which can be reversed by a mesenchymal
to epithelial transition (MET), leading to epithelial redifferentiation. A potential reinitiation of EMT is indicated
(broken arrow). It is important to note that stem-cell markers can be detected in both phases. L1CAM, L1
cell adhesion molecule; MMP14, matrix metalloproteinase 14.
in comparison to stemness, the irregular
activation of EMT might depend on further
aberrant signals. In the case of colorectal
tumours, low levels of nuclear β-catenin,
owing to APC-mutations that result in the
reduced degradation of β-catenin, might
be enough to produce inappropriate stemcell-like behaviour (and so the tumour cells
become SCS cells), thereby inducing the
earliest stage of tumorigenesis and leading to the formation of benign adenomas.
However, low-level expression of β-catenin
in the nucleus alone is not enough to trigger EMT. The EMT programme might
have a higher activation threshold that can
be overcome either by further mutations
(genetic progression) or unusual signals
from the environment at the invasive
front (dynamic progression), resulting in
MCS cells. Such changes can lead to higher
levels of nuclear β-catenin. For instance,
it was shown that the binding of extracellular matrix to β1-integrin activates
integrin linked kinase (ILK), which then
leads to further nuclear accumulation of
β-catenin44. In addition, co-stimulatory signals can come from the microenvironment
at the tumour host interface, which is often
strongly infiltrated by cytokine-producing
inflammatory cells such as granulocytes
and macrophages. Secreted microenvironmental factors that can induce EMT
include hepatocyte growth factor (HGF),
epidermal growth factor (EGF) 18 and,
in particular, TGFβ 30,45,46, which induces
EMT in cooperation with RAS signalling.
Therefore, tumour infiltrating cells might
be a decisive trigger for the switch of SCS
cells to MCS cells. In typical colorectal
cancers, we favour environmental signals
over genetic alterations as inducers of EMT
because a reduction of such signals in the
new microenvironment at the metastatic
site could explain the reversal of EMT and
the observed epithelial differentiation in
many metastases.
What can the MCS-cell concept tell us?
The MCS-cell model could potentially
answer some important open questions about
the tumorigenic process and is therefore
relevant to many aspects of human cancer
progression.
What is the decisive step from benign to
malignant growth? In the MCS-cell concept,
the decisive step is not necessarily clonal
selection based on further mutations, but
might be the crossing of an environmental
border, which leads to aberrant signals and
the subsequent induction of EMT. Some
established facts can be explained by this
view. Benign colon adenomas always grow
within the mucosal layer, and detachment of
single tumour cells and EMT are not evident,
indicating that adenomas would be unlikely
to have MCS cells. This could explain why
adenomas do not metastasize. EMT first
becomes apparent during the transition of
adenoma to carcinoma when the tumour
crosses the lamina muscularis mucosae, a thin
layer of muscle that separates mucosa from
submucosa (FIG. 4a) and metastases are only
found from this stage onwards. The number
of tumour cells at the tumour–host interface
that are associated with EMT or which express
high levels of nuclear β-catenin is correlated
with metastasis and poor survival (REFS 42,43
and T.B., A.J., S.S., F.H. and T.K. unpublished
observations), which further supports a
decisive role of these potential MCS cells in
malignant tumour progression. Furthermore,
in support of an environmental trigger, EMT
occurs all along the tumour–host interface
of carcinomas, and does not appear to be a
clonal process. Future research is needed to
illustrate whether aberrant signals initiate and
drive malignancy by the transient induction
of MCS cells from SCS cells.
How can metastases recapitulate the heterogeneity in differentiation and morphology of
the primary tumour? In both primary carcinomas and metastases, a graduated, often
concentric, epithelial differentiation is clearly
detectable (FIG. 1). This can be explained by
the MCS concept, which proposes that large
parts of the primary tumour mass and the
metastasis derive from the same pool of
MCS cells. So, we interpret the invasive carcinoma front as a kind of ‘germ-cell layer’ of
radially migrating MCS cells, which asymmetrically divide, leaving behind proliferating and differentiating tumour cells (FIG. 4).
The main difference between the primary
tumour and the metastases would only be
the distance and mode of migration — short
distances enhance the growth of the primary
tumour, and long distances (through blood
or lymphatic vessels) lead to metastases.
This implies a completely new, inverted
view of how carcinomas and metastases
grow and invade. In this scenario, dedifferentiated tumour cells have not necessarily
just detached from the tumour mass at the
invasive front, but the differentiating and
proliferating tumour mass is partly derived
from a migrating front of existing MCS cells.
Because this is applicable for both the primary tumour and for metastasis, the basic
growth principle for these tumour stages is
the same and so too is the morphology and
the grade of achievable differentiation.
How can we explain tumour-cell dormancy
and disease recurrence? The dormancy of
tumour cells can be explained by a lack of
environmental signals that induce differentiation of disseminated MCS cells, or direct
stimulation of growth arrest in MCS cells
(which is an attribute of many stem cells).
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A
Normal
colon
Early adenoma
Late adenoma
Carcinoma
Mucosa
Submucosa
B
Primary tumour
therefore the most dangerous cells for the
patients. It might prove useful to selectively
target pathways and molecules that induce
the MCS-cell phenotype by combining specific drugs against the Wnt pathway (or other
pathways associated with stemness) and
against components active in the EMT pathway (such as ILK, SNAIL (SNAI1), SLUG,
ZEB1 (also known as TCF8) TWIST1) might
prove useful. Another realistic target could
be tumour infiltrating macrophages and
lymphocytes, which might not necessarily
be anti-tumorigenic but could instead support tumour progression by secreting EMTinducing cytokines. Another option could be
the inhibition of differentiation and MET in
disseminated MCS cells to keep them in a
growth arrested (dormant) state.
Metastasis
The MCS-cell concept in other tumours?
a
b
c
Metastasis
Normal stem cell
Direction of differentiation
Lamina muscularis mucosae
Stationary cancer stem cell
Direction of migration
Tumour host interface
Migrating cancer stem cell
Distant migration
Differentiated tumour areas
Differentiating daughter cell
Figure 4 | The migrating cancer stem (MCS)-cell concept. A | Normal stem cells are located in basal
crypt areas of normal colon mucosa. Stationary cancer stem (SCS)-cells are embedded in benign
adenomas and might still be detectable in differentiated central areas of carcinomas and metastases
(corresponding to phase I, see FIG. 3). A decisive step towards malignancy is the induction of epithelial to
mesenchymal transition (EMT) (corresponding to phase II, see FIG. 3) in tumour cells, including SCS-cells,
which now become mobile, migrating cancer stem (MCS)-cells. This step could be activated by aberrant
environmental signals (in late stage colorectal adenomas this would correlate with the crossing of the
border between the mucosa and the submucosa (lamina muscularis mucosae)). B | Detailed view of the
potential function of MCS cells in carcinomas and metastases. MCS cells divide assymetrically; one
daughter cell starts proliferation and differentiation (a). The remaining MCS cell either migrates a short
distance before undergoing a new asymmetric division, thereby adding mass to the primary tumour (b), or
eventually starts long-range dissemination through blood or lymphatic vessels and produces a metastasis
after subsequent asymmetric divisions at its new location (c). Therefore, the basic mechanisms are the
same for primary carcinomas and metastases.
Recent publications describe the potential of
EMT-associated transcriptional repressors,
such as SLUG, to induce growth arrest and
resistance to apoptosis induced by chemotherapy47,48, which would explain the growth
arrest that we described for the EMT-associated tumour cells (potential MCS cells) at the
invasive front3,33. This could also explain cancer-cell dormancy, which is evident as cellular
rests in cancers, or as cells that have disseminated but have not expanded to metastases in
their new setting. Moreover, such cells might
be more resistent to standard chemotherapy
that targets proliferating cells, and therefore
could be responsible for disease recurrence.
Changes in the environment that surrounds
these cells, such as inflammation and hormonal status, might later induce proliferation
and differentiation (MET) of disseminated
MCS cells, leading to both primary tumour
recurrence and metastatic growth.
If the model can be proved, MCS cells
would be ideal tumour targets because
they are the main seed for metastasis and
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Both stemness and EMT are implicated
in the genesis of an increasing number of
human cancers. In addition, as we have discussed for colorectal cancer, metastases from
many other carcinomas recapitulate the morphology of the primary tumours. This fact
has been used for diagnostic purposes by
pathologists for a long time and indicates that
metastases are part of a dynamic and reversible system. Breast cancer metastases are a
case in point. Breast cancer is the first human
carcinoma for which cancer stem cells have
been isolated24. Ductal invasive carcinomas
of the breast show heterogeneity of intratumour differentiation, including dissociation of invasive tumour cells in an EMT-like
state. Moreover, expression of TWIST1, an
EMT-inducing transcriptional repressor that
is associated with invasive lobular breast cancer49, the EMT49,50 and associated tumour cell
dissemination27, is correlated with malignant
progression and a poor clinical prognosis51.
Therefore, breast cancer is an further example that fits both aspects (cancer stem cells
and EMT) of the MCS-cell concept. Other
tumours, for which intra-tumour heterogeneity and EMT are detectable, include pancreatic cancer52, the intestinal type of gastric
cancer53 and squamous cell carcinomas54.
Different EMT-inducing transcriptional
repressors55, such as SNAIL, SLUG, TWIST1
and SMAD interacting protein 1 (SIP1) are
expressed in these tumour types. Moreover,
disseminated tumour cells can be detected
in many solid cancers, and their presence
predicts the subsequent occurrence of
metastases56. An aberrant induction of putative cancer stem cells is indicated by the fact
that not only mutations in the Wnt pathway,
but also in other pathways associated with
the formation of stem cells in development,
PERSPECTIVES
such as the Hedgehog and Notch pathways,
are found in many cancers1. Although in
this article we have focused on environmental signals that drive EMT and subsequent
MCS-cell formation, we do not exclude
the accumulation of mutations as a driving
force in other tumours. In particular, poorly
differentiated and anaplastic carcinomas,
in which no re-differentiation is detectable
in primary tumours and metastases, might
indicate a predominantly genetic type of
tumour progression.
Summary
The MCS-cell concept of tumour progression
integrates observations in human cancers and
existing mouse models. Its hallmark is the
existence of mobile cancer stem cells, which
transiently develop from stationary cancer
stem cells by combining two decisive features:
stemness and EMT. The concept further integrates both genetic alterations and the tumour
environment as combined driving forces of
malignant progression. We are convinced
that this concept can influence both basic and
clinical cancer research, including new treatment concepts, and we therefore encourage
its verification in different models of tumour
progression and in various types of human
cancer. The identification of more specific
and precise stem cell markers should help to
isolate MCS cells from human tumours and
prove the concept.
Department of Pathology, University of Erlangen,
Krankenhausstr. 8-10, 91054 Erlangen, Germany
Correspondance to T.B.
e-mail: thomas.brabletz@
patho.imed.uni-erlangen.de
doi:10.1038/nrc1694
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Acknowledgements
The authors would like to acknowledge funding from the German
Research Council (DFG), the National Genomic Research
Network (NGFN), the Deutsche Krebshilfe and the SanderStiftung.
Competing interests statement
The authors declare no competing financial interests.
Online links
DATABASES
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
APC | CDKN2A | CCND1 | EGF | HGF | ILK | L1CAM | LAMC2 |
SIP1 | SLUG | SNAI1 | TCF4 | TCF8 | TWIST1
Cancer.gov: http://www.cancer.gov
colorectal cancer | breast cancer
Access to this interactive links box is free online.

Migrating cancer stem cells — an integrated concept of malignant

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