Review
TGF-β signaling: positive and negative effects on tumorigenesis

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Abstract

TGF-β binding to the cell surface triggers activation of multiple signal transduction pathways that are connected in intricate ways with each other, and with other response networks involved in sensing cellular information input. Recent data indicate that changes in signal intensity and connectivity of these pathways may underlie the complex transition of the TGF-β pathway from tumor suppressor to oncogene during 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

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