ReviewTGF-β signaling: positive and negative effects on tumorigenesis
Introduction
The role of TGF-β family members in carcinogenesis is complex. Originally named for their transforming activities in in vitro assays, TGF-βs now unequivocally demonstrate both tumor suppressor and oncogenic activities (Fig. 1). In the current paradigm, the suppressor activities dominate in normal tissue, but during tumorigenesis, changes in TGF-β expression and cellular responses tip the balance in favor of its oncogenic activities 1., 2., 3.. In epithelia, this process usually involves a decreased or qualitatively altered responsiveness of the tumor cell to TGF-β and increased secretion and/or activation of the TGF-β ligand. As nearly all cells both produce and respond to the ligand, understanding the roles of TGF-β in tumorigenesis requires insight into the changing response patterns of many interacting cell types, including those of the stroma. New therapeutic opportunities may emerge from a clearer definition of the molecular and cellular contexts that are permissive for the tumor suppressor versus oncogenic activities of TGF-βs. Here we review advances over the past year that provide new insights into these issues.
Section snippets
TGF-β signaling: not just Smads
TGF-βs 1–3 are secreted in latent forms, which must be activated for binding to the signaling receptors. Signaling is mediated by a heterotetrameric complex of two trans-membrane receptor serine/threonine kinases, consisting of a type II ligand binding receptor (TβRII) and a type I signaling receptor (TβRI). Smads 2 and 3 are direct substrates of TβRI and, together with the common mediator, Smad4, play key roles as cytoplasmic signaling mediators. Although the Smad pathway has received much
Tumor suppression: beyond growth inhibition
Multicellular organisms have many mechanisms for protection against tumorigenesis. In addition to tight control of the cell cycle, the cell must monitor and maintain the integrity of its genetic information; sense and respond to aberrant oncogenic activation through suicide or forced senescence; maintain tight control of genes determining cellular lifespan; and continually assess its appropriate functional and spatial relationship with other cells. Recent work has implicated TGF-β molecules in
Dosage effects in the TGF-β pathway
Classically, both alleles of a tumor suppressor gene must be inactivated for a tumor to form. Possibly because of its dual tumor suppressor and oncogenic roles, the TGF-β pathway does not appear to operate in this simple On/Off manner, but shows rather complex dosage effects. In mice, loss of just one allele of TGF-β1 is sufficient to relieve growth inhibition and compromise tumor suppressor function, leading to the prediction that variations in TGF-β1 levels might affect susceptibility to
Tumor suppression versus oncogenesis
It is now recognized that TGF-βs have pro-oncogenic effects that directly target the tumor cell itself, in addition to the indirect effects on the stromal compartment (Fig. 1). Chief among these are mechanisms for enhancement of invasion and metastasis. As total genetic inactivation of the TGF-β pathway in the tumor cell would compromise these pro-oncogenic functions, tumor cells have evolved more subtle strategies for selectively disabling the suppressor responses, while either retaining or
Therapeutic opportunities
From a TGF-β standpoint, the therapeutic challenge in cancer becomes the issue of how to restore lost tumor suppressor function while either eliminating or preventing acquired pro-oncogenic effects. Late-stage invasive, metastatic disease is typically characterized by locally or systemically elevated TGF-β levels, coupled with diminished responsiveness of tumor cells to its suppressor functions 1., 2.. As examples, increased activation of latent TGF-β in the tumor microenvironment by
Conclusions
Given the contextuality both of the specific signaling pathways activated by TGF-β and of the responses of cells as they progress to an invasive phenotype, it will be important not only to continue to use sophisticated molecular approaches in vitro, but also to intensify efforts to extend these investigations to more complex in vivo models. How is the molecular context of a cell altered in tumorigenesis so as to constrain the TGF-β signal, and how does this process vary between tissues? Why is
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
References (63)
- et al.
TGFbeta signaling in growth control, cancer, and heritable disorders
Cell
(2000) - et al.
Role of Smad proteins and transcription factor Sp1 in p21(WAF1/Cip1) regulation by transforming growth factor-beta
J Biol Chem
(2000) - et al.
Targeted disruption in murine cells reveals variable requirement for Smad4 in transforming growth factor beta-related signaling
J Biol Chem
(2000) - et al.
The MEK pathway is required for stimulation of p21(WAF1/CIP1) by Transforming Growth Factor-beta
J Biol Chem
(1999) - et al.
Site-dependent production of transforming growth factor beta1 in colonic mucosa: its possible role in tumorigenesis of the colon
J Lab Clin Med
(2000) - et al.
TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis
Curr Biol
(1998) - et al.
Molecular mechanisms of inactivation of TGF-beta receptors during carcinogenesis
Cytokine Growth Factor Rev
(2000) - et al.
Oncogenic Ki-ras confers a more aggressive colon cancer phenotype through modification of transforming growth factor-beta receptor III
J Biol Chem
(2001) - et al.
Involvement of the Ras/MAPK signaling pathway in the modulation of urokinase production and cellular invasiveness by transforming growth factor-beta(1) in transformed keratinocytes
Biochem Biophys Res Commun
(2000) - et al.
Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration
J Biol Chem
(2000)
Oncogenic ras represses transforming growth factor-beta/mad signaling by degrading tumor suppressor smad4
J Biol Chem
Ultraviolet irradiation blocks cellular responses to transforming growth factor-beta by down-regulating its type-II receptor and inducing Smad7
J Biol Chem
The two-handed E box binding zinc finger protein SIP1 downregulates E- cadherin and induces invasion
Mol Cell
Functional cloning of the proto-oncogene brain factor-1 (BF-1) as a Smad-binding antagonist of transforming growth factor-beta signaling
J Biol Chem
Different sensitivity of the transforming growth factor-beta cell cycle arrest pathway to c-Myc and MDM-2
J Biol Chem
Captopril restores transforming growth factor-beta type II receptor and sensitivity to transforming growth factor-beta in murine renal cell cancer cells
J Urol
Role of transforming growth factor-beta signaling in cancer
J Natl Cancer Inst
TGF-beta signaling in mammary gland development and tumorigenesis
J Mammary Gland Biol Neoplasia
Transforming growth factor beta 1 suppression of c-myc gene transcription: role in inhibition of keratinocyte proliferation
Proc Natl Acad Sci USA
Defective repression of c-myc in breast cancer cells: a loss at the core of the transforming growth factor beta growth arrest program
Proc Natl Acad Sci USA
Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta
EMBO J
TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b
Nat Cell Biol
A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta-induced cell-cycle arrest
Proc Natl Acad Sci USA
Transforming growth factor-beta-induced growth inhibition in a Smad4 mutant colon adenoma cell line
Cancer Res
TGFbeta1 represses proliferation of pancreatic carcinoma cells which correlates with Smad4-independent inhibition of ERK activation
Oncogene
TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G1 arrest
Genes Dev
Transforming growth factor beta 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb
Cancer Res
Autocrine transforming growth factor beta suppresses telomerase activity and transcription of human telomerase reverse transcriptase in human cancer cells
Cell Growth Differ
Defects in TGF-beta signaling overcomes senescence of mouse keratinocytes expressing v-Ha-ras
Oncogene
Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis
Cancer Res
Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis
Proc Natl Acad Sci USA
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