28 TGF-β Signaling Pathway and Tumor Suppression

Transforming growth factor β (TGF-β) is the prototype member of a family of secreted proteins that include the three TGF-β isoforms (TGF-β1, TGF-β2, and TGF-β3), activins, growth and differentiation factors (GDFs), bone morphogenetic proteins (BMPs), inhibins, nodal, and anti-Mullerian hormone. These ligands all mediate biological activities in cells through binding to heteromeric receptor complexes at the cell surface that are composed of type I and type II receptors. The TGF-β family has been the subject of intense investigation since its discovery, and these studies have revealed roles for TGF-β signaling in development and cancer biology. In epithelial cells, TGF-β inhibits cell proliferation, induces apoptosis, and mediates differentiation, which suggests that this pathway has tumor-suppressor activities in epithelial tumors. Accordingly, a large body of evidence has established that elements of the TGF-β signaling pathway have a prominent role as tumor-suppressor genes in neoplasms originating from epithelial tissues, particularly gastrointestinal tract cancers. Conversely, other studies provide evidence that in certain contexts, TGF-β promotes the invasive or metastatic behavior of established cancer cells, suggesting that TGF-β paradoxically can have opposing roles in human cancers that appear to depend on the stage of the cancer. This chapter focuses on the tumor-suppressor activity of the TGF-β signaling pathway with an emphasis on the deregulation of TGF-β signaling in gastrointestinal malignancies, the organ system in which tumor-suppressor effects have been most clearly demonstrated. OVERVIEW OF TGF-β SIGNALING PATHWAY ELEMENTS AND ROLE IN TUMOR SUPPRESSION TGF-β is a multifunctional cytokine that induces growth inhibition, apoptosis, and differentiation...