TGF-β Signaling in Cancer

The transforming growth factor- (TGF-) is a family of structurally related proteins that comprises of TGF-, activins/inhibins, and bone morphogenic proteins (BMPs). Members of the TGF- family control numerous cellular functions including proliferation, apoptosis, differentiation, epithelial-mesenchymal transition (EMT), and migration. The first identified member, TGF- is implicated in several human diseases, such as vascular diseases, autoimmune disorders, and carcinogenesis. Activation of the TGF- receptor by its ligands induces the phosphorylation of serine/threonine residues and triggers phosphorylation of the intracellular effectors, SMADs. Upon activation, SMAD proteins translocate to the nucleus and induce transcription of their target genes, regulating several cellular functions. TGF- dysregulation has been implicated in carcinogenesis. In early stages of cancer, TGF- exhibits tumor suppressive effects by inhibiting cell cycle progression and promoting apoptosis. However, in late stages TGF- exerts tumor promoting effects, increasing tumor invasiveness, and metastasis. Furthermore, the TGF- signaling pathway communicates with other signaling pathways in a synergistic or antagonistic manner and regulates cellular functions. Elevated TGF- activity has been associated with poor clinical outcome. Given the pivotal role of TGF- in tumor progression, this pathway is an attractive target for cancer therapy. Several therapeutic tools such as TGF- antibodies, antisense oligonucleotides, and small molecules inhibitors of TGF- receptor-1 (TGF-R1) have shown immense potential to inhibit TGF- signaling. Finally, in the interest of developing future therapies, further studies are warranted to identify novel points of convergence of TGF- with other signaling pathways and oncogenic factors in the tumor microenvironment. J. Cell. Biochem. 117: 1279-1287, 2016. (c) 2016 Wiley Periodicals, Inc.