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INVITED REVIEW
*Correspondence to: Peter ten Dijke, Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center,
Building 2, Room R-02-022, Postzone S-1-P, Postbus 9600, 2300 RC, Leiden, The Netherlands e-mail: p.ten_dijke@lumc.nl
Abstract
The transforming growth factor- (TGF-) signalling pathway plays a critical and dual role in the progression of
human cancer. During the early phase of tumour progression, TGF- acts as a tumour suppressor, exemplified
by deletions or mutations in the core components of the TGF- signalling pathway. On the contrary, TGF- also
promotes processes that support tumour progression such as tumour cell invasion, dissemination, and immune
evasion. Consequently, the functional outcome of the TGF- response is strongly context-dependent including
cell, tissue, and cancer type. In this review, we describe the molecular signalling pathways employed by TGF-
in cancer and how these, when perturbed, may lead to the development of cancer. Concomitantly with our
increased appreciation of the molecular mechanisms that govern TGF- signalling, the potential to therapeutically
target specific oncogenic sub-arms of the TGF- pathway increases. Indeed, clinical trials with systemic TGF-
signalling inhibitors for treatment of cancer patients have been initiated. However, considering the important
role of TGF- in cardiovascular and many other tissues, careful screening of patients is warranted to minimize
unwanted on-target side effects.
Copyright 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Keywords: BMP; cancer; epithelial to mesenchymal transition; EMT; metastasis; signal transduction; Smad; TGF-; ubiquitin
Introduction
Transforming growth factor- (TGF-) emerged with
the evolution of multi-cellular organisms, where it
plays an essential role in the development of the
body plan during embryogenesis and is crucial for tissue homeostasis. The TGF- pathway mediates such
regulation through control of proliferation, differentiation, apoptosis, adhesion, invasion, and cellular microenvironment [14]. Consequently, malfunctioning of
this pathway has adverse effects and inactivation of
components in this signalling pathway is central to
many diseases including the development of tumourigenesis and tumour progression. In several types of
human carcinomas, mutations or loss of heterozygosity (LOH) in central components of the TGF-
pathway has been observed [5]. These observations
support the idea that the TGF- pathway has a tumoursuppressive role that needs circumvention to allow
tumourigenesis. Also, due to its growth-suppressive
effects, in the past TGF- itself has been regarded
as an attractive cytokine for the treatment of cancer. Therefore, studies were initiated in which TGF-
was explored as an adjuvant for chemotherapy. Indeed,
TGF- was able to protect normal cells and sensitize
tumour cells towards standard chemotherapy in some
Copyright 2010 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
pre-clinical models [6,7]. Nonetheless, issues with dosing and timing of TGF- treatment, among others,
halted the translation of these findings towards clinical
application.
Importantly, analysis of human tumour samples
has also suggested an active role for the TGF-
pathway in tumour progression. Immuno-staining for
TGF- correlated with metastasis in breast, colon,
and prostate cancer [810]. In addition, the intensity
of TGF- staining in invading lymph node metastases was higher in breast and colon cancers than
in the primary tumour [11,12]. Moreover, TGF-
increases the motility and invasion of certain cancer cells, demonstrating that these cells, while having lost sensitivity for TGF--induced growth arrest,
remained TGF--responsive [13]. Furthermore, TGF secreted by tumour cells stimulates stroma formation and immune evasion of tumour cells [14,15].
Thus, TGF- has both tumour-suppressive and tumourpromoting functions [16]. In this review, we will
elaborate on the dynamic role that TGF- plays in
cancer biology; how perturbation of the TGF- signalling pathways contributes to cancer; and how new
insights provide opportunities for targeted therapy of
cancer patients.
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Non-canonical signalling
While canonical signalling directly regulates the transcription of Smad-dependent target genes, Smad
proteins have also been shown to participate in sequestration, recruitment, and enzyme activation [6163].
R-Smads (independent of Smad4) are also involved in
the regulation of miRNA maturation in the nucleus
[64]. Moreover, alternative signalling modules are
present in parallel with Smad signalling that are
also responsive to TGF-. The existence of Smadindependent signalling is supported by the identification of the TRAF6TAK1p38/JNK pathway as
a TGF- signalling module downstream of TGF-
receptors [6567]. Furthermore, TGF- signalling is
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TGF- in cancer
207
Figure 1. The TGF- signalling pathway. Transforming growth factor- (TGF-) present in the extracellular matrix resides in the large
latent complex (LLC). Upon release, active TGF- weakly interacts with the large betaglycan membrane protein that is present in vast
excess compared with TGF-RII. Subsequently, TGF- is presented to TGF-RII, which leads to the formation of a heterotetrameric
complex between the serine/threonine kinases TGF-RI and TGF-RII. The constitutive active TGF-RII phosphorylates (P) TGF-RI, which
in turn recruits, phosphorylates, and activates Smad transcription factors (Smad2/3). Phosphorylated Smad2/3 form a complex with the
co-Smad (Smad4), translocate into the nucleus, and further build transcription complexes with additional co-repressors or co-activators to
regulate the expression of a wide variety of genes. The inhibitory Smad (Smad7) reduces further signalling by preventing phosphorylation
of Smad2/3. Besides Smad-mediated signalling, TGF- also activates several other signalling cascades such as TRAF6TAK1p38/JNK,
RhoARhock1, and Par6.
208
been observed in pancreas, ovarian, and breast cancer [7779]. Downstream of the receptors, inactivating
mutations or deletions of SMAD4 are present in half
of the pancreatic tumours and to a lesser extent in gastrointestinal tumours [75,78]. However, tissue-specific
inactivation of Smad4 or TGF-RII alone in mouse
models rarely leads to spontaneous tumour formation, suggesting that the outcome of interference with
TGF- signalling is strongly dependent on the context
of individual tumours [8085]. In fact, the tumoursuppressive role of TGF- is most apparent under
conditions of oncogenic stress. For example, inactivation of Smad4 or TGF-RII in adenomatosis polyposis
coli (APC)-deficient mice potentiates the progression
of intestinal polyps to carcinoma [83,86]. Similarly,
mammary tumours initiated by polyoma virus middleT oncogene and premalignant lesions initiated by the
KRAS oncoprotein in skin, pancreas, and oral and
oesophagus epithelium progress faster when TGF-
signalling is crippled [8082,84].
Mechanistically, TGF- has several operating arms
to achieve its tumour-suppressive effect which include
regulation of cell proliferation, apoptosis, and indirectly through the tumour stroma.
Figure 2. TGF- as a tumour suppressor. (A) TGF- controls cell cycle progression by repressing the oncogenic Myc transcription factor,
which in turn prevents transcriptional activation of the CDK inhibitors p21 and p15 via interaction with MIZ1. TGF- also directly
transcriptionally activates p21 and p15. p15 abolishes the interaction of cyclin D (Cyc D) with the CDK4/6 complex, thereby inactivating
the CDK. p21 (and also p27) inactivates the cyclin E (Cyc E) CDK2 complex, which leads to stalling of the cell cycle at the G1S boundary.
(B) TGF- inhibits apoptosis in a variety of cell types; however, the exact molecular mechanisms remain to be determined. (C) Through
non-cell autonomous signalling, TGF- controls tumour progression via inhibition of paracrine growth factors in the tumour stroma during
the early stages of tumour development. The absence of TGF- signalling in tumour stroma cells relieves the growth inhibitory effect on
epithelial cells, which consequently obtain increased growth, migratory, and invasive properties.
Copyright 2010 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
TGF- in cancer
209
subsets of colon, pancreatic, and gastric cancers, mutation or deletion of TGF- receptors or Smads in
the TGF- pathway leads to its inactivation or perturbation of signalling responses [7476,107110].
Tumours that acquire the ability to bypass the tumoursuppressive arms may exploit certain aspects of TGF-
signalling to actively promote tumour cell progression.
In fact, aggressive tumours resistant to the tumoursuppressive effects of TGF- preserve the core components of TGF- signalling. Different types of tumours
such as gliomas and breast and prostate cancer seem to
acquire mutations preferentially not in the core components of TGF- signalling [109,111114]. Such human
tumours likely obtain resistance to TGF--mediated
growth arrest and importantly retain the ability to
exploit TGF- signalling to induce pathways that promote EMT, tumour invasion, metastatic dissemination,
and evasion of the immune system. Therefore, tumours
with such a signature are highly aggressive.
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Figure 3. TGF- as a tumour promoter. (A) TGF- stimulates the progression of carcinoma in situ towards a more aggressive, motile, and
invasive carcinoma. The tumour cells (yellow) acquire the capacity to invade adjacent tissues and intravasate into the blood stream.
(B) TGF- promotes metastatic dissemination of primary breast carcinoma towards bone by up-regulating PTHrP and IL11, which in turn
activate osteoblasts (green) to secrete RANKL. RANKL leads to the differentiation of precursor cells (blue) into osteoclasts (orange), which
absorb the bone mass and release stored TGF-. As such, a feed-forward loop is created in which TGF- promotes the growth of bone
metastasis. (C) By inducing ANGPTL4, TGF- primes tumour cells for dissemination towards the lungs. ANGPTL4 enhances extravasation
by dissociating vascular endothelial cellcell junctions. TGF-, released by the tumour cells, allows evasion of the immune response by
inactivating CD4+ and CD8+ T-cells that normally inhibit the growth of tumour cells.
TGF- in cancer
Metastatic dissemination
After invasion into adjacent tissue, the metastatic
process continues through intravasation, dissemination
to distal capillary beds, extravasation, and growth in a
distal organ [136,137]. Particular tumour types have a
tendency to metastasize to certain organs; for example,
breast tumours tend to metastasize towards the brain,
lungs, bones, and liver. This distribution pattern seems
to be dependent on the expression of a specific set of
genes rather than vasculature, blood flow, and number
of cells delivered to the receiving organ [138140].
The role of TGF- in the metastatic process became
evident with the observation that TGF- immunostaining was much stronger in metastasized breast
tumours than in the primary tumour [11]. In addition,
expression of TGF-RII has a negative correlation with
overall survival in oestrogen receptor (ER)-negative
breast cancer patients [141]. Importantly, chemotherapy or radiation treatment in the MMTV/PyVmT transgenic model of breast metastasis led to increased TGF1 levels as well as increased circulating tumour cells
and lung metastasis [142]. Administration of neutralizing TGF- antibodies prevents this increase in metastasis, thus suggesting an important role for TGF- in the
metastatic process [142]. However, the role of TGF-
in metastasis progression seems to be strongly contextdependent. For example, expression of an activated
TGF-RI transgene increases metastasis to the lungs,
while targeted deletion of TGF-RII resulted in a similar observation [80,143,144]. The picture of TGF-
as a promoter of metastasis is even further obscured
by the observation that short-term stimulation with
TGF- stimulates metastasis formation, while persistent stimulation decreases the metastatic spread to the
lungs [145]. From this study, it has been proposed that
TGF- signalling initially needs to be high in order
to acquire invasive properties for dissemination, while
upon extravasation TGF- signalling is low to allow
proliferation at the secondary site.
Insights into the mechanism by which TGF- stimulates metastatic dissemination came from studies on
bone and lung metastasis. Primary breast and prostate
tumours have in common that they often metastasize
towards bone, a process in which TGF- plays an
important role upon the arrival of tumour cells. The
presence of metastatic tumour cells in the bone microenvironment leads to activation of osteoclasts, which
degrade the bone matrix and consequently release
stored TGF- and other growth factors. TGF- in
turn stimulates the metastatic cells to release osteolytic cytokines such as, amongst others, parathyroid
Copyright 2010 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
211
hormone-related protein (PTHrP) [146,147]. The posttranslationally increased levels of PTHrP subsequently
stimulate production of RANK ligand (RANKL) in
osteoblasts, which in turn promotes the differentiation of osteoclast precursors and bone resorption
(Figure 3B) [148,149]. Furthermore, it was recently
demonstrated that TGF-RII also directly phosphorylates the PTH receptor and via this route could also
contribute to bone resorption [72].
Transcriptome comparison, of adrenal with bone
metastasis, originated from a breast cancer epithelial
cell line inoculated into mice, led to the identification
of CTGF and IL-11 within a larger gene signature as
critical factors for bone metastasis [138]. The TGF-mediated induction of IL-11 and CTGF, as well
as the acquired metastatic capacity, requires Smad4dependent signalling [123,150]. Besides Smad4, Smad3
is required for the induction of key target genes
in metastasis [151]. Importantly, depletion of Smad2
enhanced the metastatic process of MDA-MB-231
cells, while Smad3 prevented the metastatic spread
[151].
Besides stimulating metastatic colonization, TGF-
also has the ability to prime tumour cells for metastatic
dissemination. By employing a cell culture-derived
TGF- gene response signature, angiopoietin-like 4
(ANGPTL4) was identified as a key player to prime
breast cancer cells for metastasis towards the lungs
[152]. ANGPTL4 assists the tumour cells to disrupt
the lung capillaries and thereby enables pulmonary
metastasis (Figure 3C). In a previous study ANGPLT4
has also been identified within a TGF--responsive
gene signature that mediates metastasis towards the
lungs [139]. The presence of dominant negative TGFRI or the absence of Smad4 in ER-negative breast
cancer cells prevented their capacity to metastasize
when implanted as mammary tumours.
These studies shed light on a role for TGF- in
the metastatic process, both in the early invasion and
intravasation stage and during the later process involving extravasation and colony formation. However, most
of these studies rely on either inoculation of cell
lines or transplantation of tumours. For future work,
it would be important to study these phenomena in a
more physiological setting employing mouse models in
which metastases arise spontaneously from the primary
tumour. In such a setting, the role of TGF- in the various metastatic processes for different types of cancer
could be investigated employing inducible knockout or
knock-in models.
Immune evasion
In addition to regulation of EMT, invasion, and
metastatic dissemination, TGF- also supports tumour
progression by evading the immune system [2]. The
first evidence for TGF- in immune evasion came
from the observation that TGF- potently inhibits
tumour-induced CD8+ cytolytic T-lymphocyte (CTL)mediated rejection of a murine tumour [153]. Further
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212
the production of the ectopic TGF- is by using antisense molecules, which block TGF--mediated gene
expression. Antisense molecules for TGF-1 demonstrate promising results in pre-clinical experiments
by decreasing tumourigenicity [163,164]. A promising
candidate in further development is AP 12 009 (Antisense Pharma), an antisense molecule directed against
TGF-2, which reduces TGF-2-mediated migration
and proliferation, as well as alleviating its immunosuppressive effects [165,166]. The efficacy in phase
I/II clinical trials to treat refractory high-grade glioma
patients exceeded the expected median survival compared with chemotherapy [166]. These results suggest
AP 12 009 as a promising therapeutic target to inhibit
TGF- signalling for malignant tumour therapy. Currently, AP 12 009 is in further clinical studies to test
its efficacy for metastatic melanoma, pancreatic carcinoma, and metastatic colorectal carcinoma.
TGF- in cancer
Acknowledgment
We are grateful to all laboratory members for stimulating discussions. We apologize to those whose work
we could not cite due to limited space constraints.
Our work is supported by grants from the LUMC
(vrije beleidsruimte), the Dutch Cancer Society, the
Netherlands Organization for Health and Development,
the Swedish Cancer Foundation, and the Centre for
Biomedical Genetics.
213
Teaching materials
PowerPoint slides of the figures from this review
are supplied as supporting information in the online
version of this article.
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