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Cell cycle Features
Cell cycle Features
Cell Cycle 8:23, 3787-3805; December 1, 2009; © 2009 Landes Bioscience
TGFβ and cancer initiating cells
Joan Seoane
Vall d’Hebron Institute of Oncology; Vall d’Hebron University Hospital Research Institute; Autonomous University of Barcelona; and Institució Catalana de Recerca
i Estudis Avançats (ICREA); Barcelona, Spain
Since the beginning of cancer research, it
is well known that cells within a tumor
exhibit morphological and functional
heterogeneity showing different states of
differentiation, proliferative capacities
and sensitivity to treatments. Recent data
indicate that there is yet another level of
heterogeneity. A subset of cells within the
tumor mass differs from the rest of cells in
its increased ability to initiate and recapitulate the tumor of the patient when inoculated in mice. These cells, also called cancer
stem cells or cancer initiating cells (CICs),
exhibit stem-cell like characteristics and
are not only considered to be responsible
for tumor initiation but for tumor propagation, recurrence, chemo- and radio-resistance and, in certain cases, metastasis. All
these characteristics indicate that CICs are
crucial therapeutic targets and suggest that
the understanding of the molecular mechanisms involved in CIC biology is critical
in order to design rational and successful
therapies.1-3
Several signal transduction pathways
have been implicated in the control of CICs
including the Wnt, Hh and Notch pathways. Recently, TGFβ family members
have also been involved in the regulation of
CIC biology. The TGFβ family of cytokines includes the TGFβs, BMPs, Nodal,
Activins and GDFs and is involved in the
regulation of embryonic development and
tissue homeostasis.4-6 Ligands of the TGFβ
family initiate signal transduction through
ligand-receptor interactions that converge
to nuclear accumulation of transcriptionally active Smads. In general and with
exceptions in some cell types, TGFβs,
Activins and Nodal signal through Smad2
and 3 whereas BMPs and GDFs signal
through Smad1, Smad5 and Smad8.4,5
BMP has been shown to inhibit proliferation and induce differentiation of CICs
in glioblastoma multiforme (GBM).7,8
However, not all glioblastoma initiating
cells (GICs) respond to BMP. Only GICs
from tumors with no methylation of the
BMP receptor 1b (BMPR1b) gene differentiate and stop proliferating when treated
with BMP.8 Although the mediators of
the BMP effect are not identified, BMP
is considered a putative therapeutic effector targeting GICs.7,8 On the other hand,
TGFβ induces the converse effect. TGFβ
promotes GIC self-renewal and prevents
differentiation enhancing the oncogenic
capacity of GICs, Figure 1.9 These functionally opposed responses to TGFβ and
BMP are not an uncommon phenomenon
in cell differentiation processes.10
TGFβ has an important role in
glioma.11,12 TGFβ is highly active in
aggressive gliomas and a high level of
phospho-Smad2 is a poor prognosis factor in patients indicating that TGFβ is
involved in tumor progression.12 The effect
of TGFβ on GIC self-renewal is part of the
oncogenic response to TGFβ in addition
to the capacity of TGFβ to induce proliferation, inmunosuppression, invasion
and angiogenesis.6 The regulation of GIC
self-renewal by TGFβ is mediated by LIF.
TGFβ induces LIF transcription via an
activated Smad complex that binds to the
LIF promoter and LIF, in turn, promotes
self-renewal and prevents differentiation
of GICs.9 In human patients, LIF is highly
expressed in tumors with high levels of
TGFβ2,9 and, moreover, LIF is one of the
genes present in gene expression signatures
that identify a subclass of human GBMs
with a mesenchymal phenotype.13 The
mesenchymal GBM subclass is the most
aggressive of all subclasses.
LIF is a member of the IL6 family of
cytokines and signals through an heterodimeric receptor complex formed by
the glycoprotein 130 (gp130) and the LIF
receptor (LIFR) inducing the JAK-STAT
pathway. Interestingly, IL6 itself induces
GIC proliferation and survival and blockade of IL6 inhibits tumor initiation.14
Thus, both members of the IL6 family,
LIF and IL6, share the same effect on
GICs. Of relevance, IL6 is also induced
by TGFβ in GBM (Seoane J, et al. unpublished results) indicating that IL6 might
also be a mediator of the induction of GIC
self-renewal by TGFβ, Figure 1.
The effect of TGFβ family members on
GICs has a parallelism in normal human
embryonic stem cells (ESCs). TGFβ,
Activins and Nodal promote human ESC
self-renewal whereas BMPs promote cell
differentiation.15-17 Recently, it has been
shown that the effect of TGFβ/Activin in
human ESCs is in part mediated by the
Smad-dependent induction of Nanog.18
In addition, LIF is a well studied inducer
of mouse ESC self-renewal. All these
results indicate that GICs may recapitulate similar mechanisms of self-renewal
regulation to the ones found in normal
stem cells.
The role of TGFβ and BMP in CICs
from other tumor types besides GBM has
not been fully studied. However, TGFβ
has been implicated in the regulation of
cells with stem cell-like characteristics
in breast cancer. The TGFβ-mediated
induction of an epithelial-mesenchymal
transition (EMT) in neoplastic mammary
epithelial cell populations has been shown
to result in the enrichment of a CD44high /
CD24low cell population.19,20 This cell
population presents stem cell-like characteristics including the capacity to initiate
tumors and the resistance to chemotherapy.19,21 Further studies are needed to
show whether the mechanisms that regulate GIC self-renewal have a parallel in
Correspondence to: Joan Seoane; Email: [email protected]
Submitted: 09/11/09; Accepted: 09/11/09
Previously published online: www.landesbioscience.com/journals/cc/article/10054
Comment on: Penuelas S, et al. Cancer Cell 2009; 15:315–27.
www.landesbioscience.com
Cell Cycle
3787
Figure 1. BMP induces GIC differentiation in gliomas with no methylation of the BMPR1a gene and TGFβ promotes GIC self-renewal through the
induction of LIF and IL6.
the CD44 high /CD24 low cell population
in breast tumors.
Based on the definition of CICs, this
cell population is the critical therapeutic target in cancer. The data reviewed
here indicate that compounds that
inhibit TGFβ could be effective against
CICs. The inhibition of TGFβ could
decrease the CIC pool in tumors and
might prevent tumor recurrence, resistance to chemo and radio-therapies,
and possibly metastasis. This is of great
relevance in the context of anti-TGFβ
therapies currently being developed
and tested in clinical trials. 22 However,
it is important to note that different
tumors might have CICs with different molecular characteristics and with
different responses to treatments. This
is exemplified by the fact that BMP is
3788
a differentiating factor only in the subset of CICs with no epigenetic silencing
of the BMPR1b gene. 8 Another level of
complexity comes from the possibility
that the same tumor may contain different CICs with heterogeneous characteristics. These concepts imply that
CICs within each tumor should be well
characterized prior to treatment with a
particular compound. Further work is
required to obtain CIC specific markers
in order to study the characteristics and
regulation of this cell compartment.
References
1.
2.
3.
4.
5.
6.
Marotta LL, et al. Curr Opin Genet Dev 2009;
19:15-7.
Visvader JE, et al. Nat Rev Cancer 2008; 8:755-68.
Dick JE. Blood 2008; 112:4793-807.
Schmierer B, et al. Nat Rev Mol Cell Biol 2007;
8:970-82.
Massague J, et al. Genes Dev 2005; 19:2783-810.
Massague J. Cell 2008; 134:215-30.
Cell Cycle
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Piccirillo SG, et al. Nature 2006; 444:761-5.
Lee J, et al. Cancer Cell 2008; 13:69-80.
Penuelas S, Anido J, Prieto-Sanchez RM, Folch G,
Barba I, Cuartas I, et al. TGFbeta increases gliomainitiating cell self-renewal through the induction
of LIF in human glioblastoma. Cancer Cell 2009;
15:315-27.
Watabe T, et al. Cell Res 2009; 19:103-15.
Rich JN. Front Biosci 2003; 8:245-60.
Bruna A, et al. Cancer Cell 2007; 11:147-60.
Phillips HS, et al. Cancer Cell 2006; 9:157-73.
Wang H, et al. Stem Cells 2009.
James D, et al. Development 2005; 132:1273-82.
Moses HL, et al. Curr Opin Genet Dev 1996;
6:581-6.
Pera MF, et al. J Cell Sci 2004; 117:1269-80.
Xu RH, et al. Cell Stem Cell 2008; 3:196-206.
Mani SA, et al. Cell 2008; 133:704-15.
Shipitsin M, et al. Cancer Cell 2007; 11:259-73.
Gupta PB, et al. Cell 2009; 138:645-59.
Seoane J. Clin Transl Oncol 2008; 10:14-9.
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