Transforming growth factor-β in cancer and metastasis

Abstract

Transforming growth factor-beta (TGF-β) is a multifunctional regulatory polypeptide that is the prototypical member of a large family of cytokines that controls many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival. The actions of TGF-β are dependent on several factors including cell type, growth conditions, and the presence of other polypeptide growth factors. One of the biological effects of TGF-β is the inhibition of proliferation of most normal epithelial cells using an autocrine mechanism of action, and this suggests a tumor suppressor role for TGF-β. Loss of autocrine TGF-β activity and/or responsiveness to exogenous TGF-β appears to provide some epithelial cells with a growth advantage leading to malignant progression. This suggests a pro-oncogenic role for TGF-β in addition to its tumor suppressor role. During the early phase of epithelial tumorigenesis, TGF-β inhibits primary tumor development and growth by inducing cell cycle arrest and apoptosis. In late stages of tumor progression when tumor cells become resistant to growth inhibition by TGF-β due to inactivation of the TGF-β signaling pathway or aberrant regulation of the cell cycle, the role of TGF-β becomes one of tumor promotion. Resistance to TGF-β-mediated inhibition of proliferation is frequently observed in multiple human cancers, as are various alterations in the complex TGF-β signaling and cell cycle pathways. TGF-β can exert effects on tumor and stromal cells as well as alter the responsiveness of tumor cells to TGF-β to stimulate invasion, angiogenesis, and metastasis, and to inhibit immune surveillance. Because of the dual role of TGF-β as a tumor suppressor and pro-oncogenic factor, members of the TGF-β signaling pathway are being considered as predictive biomarkers for progressive tumorigenesis, as well as molecular targets for prevention and treatment of cancer and metastasis.