TGF‐β Signaling in Cancer

The transforming growth factor‐β (TGF‐β) is a family of structurally related proteins that comprises of TGF‐β, activins/inhibins, and bone morphogenic proteins (BMPs). Members of the TGF‐β family control numerous cellular functions including proliferation, apoptosis, differentiation, epithelial‐mesenchymal transition (EMT), and migration. The first identified member, TGF‐β is implicated in several human diseases, such as vascular diseases, autoimmune disorders, and carcinogenesis. Activation of the TGF‐β 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‐β dysregulation has been implicated in carcinogenesis. In early stages of cancer, TGF‐β exhibits tumor suppressive effects by inhibiting cell cycle progression and promoting apoptosis. However, in late stages TGF‐β exerts tumor promoting effects, increasing tumor invasiveness, and metastasis. Furthermore, the TGF‐β signaling pathway communicates with other signaling pathways in a synergistic or antagonistic manner and regulates cellular functions. Elevated TGF‐β activity has been associated with poor clinical outcome. Given the pivotal role of TGF‐β in tumor progression, this pathway is an attractive target for cancer therapy. Several therapeutic tools such as TGF‐β antibodies, antisense oligonucleotides, and small molecules inhibitors of TGF‐β receptor‐1 (TGF‐βR1) have shown immense potential to inhibit TGF‐β signaling. Finally, in the interest of developing future therapies, further studies are warranted to identify novel points of convergence of TGF‐β with other signaling pathways and oncogenic factors in the tumor microenvironment. J. Cell. Biochem. 117: 1279–1287, 2016. © 2016 Wiley Periodicals, Inc.