TGF-β Signaling in Cancer: Control by Negative Regulators and Crosstalk with Proinflammatory and Fibrogenic Pathways.

The transforming growth factor-β (TGF-β) family of secreted growth factors controls many aspects of cell and tissue physiology in multicellular eukaryotes. Dysregulation of its pathway contributes to a broad variety of pathologies, including fibrosis and cancer. TGF-β acts as a powerful tumor suppressor in epithelial cells but during later stages of tumor development cancer cells eventually respond to this cytokine with epithelial-mesenchymal transition (EMT), invasion, metastasis, and immunosuppression. This collection of articles covers some important aspects of TGF-β signaling in cancer. Two articles focus on the role of TGF-β in tumor immunity and pro- and anti-inflammatory signaling, with one analyzing its impact on T-cell biology and different T-cell subsets, while the other deals with modulation of anti-inflammatory signaling by TGF-β receptors through proinflammatory signaling by immune receptors and the role of mechanotransduction in TGF-β-dependent immunosuppression. Another set of four chapters highlights the fact that context-dependent responsiveness to TGF-β is largely controlled by inputs from negative regulators and cooperation with proinflammatory and proapoptotic pathways. This theme is extended to the regulation of Smad signaling by differential phosphorylation, eventually converting canonical Smad signaling to a mitogenic, fibrogenic and carcinogenic outcome. Last, it is discussed how another posttranslational modification, SUMOylation, can modify protein function and impact TGF-β-induced EMT, invasion and metastasis.