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.