TGF-β signaling: A recap of SMAD-independent and SMAD-dependent pathways

Transforming growth factor-beta (TGF-beta) is a proinflammatory cytokine known to control a diverse array of pathological and physiological conditions during normal development and tumorigenesis. TGF-beta-mediated physiological effects are heterogeneous and vary among different types of cells and environmental conditions. TGF-beta serves as an antiproliferative agent and inhibits tumor development during primary stages of tumor progression; however, during the later stages, it encourages tumor development and mediates metastatic progression and chemoresistance. The fundamental elements of TGF-beta signaling have been divulged more than a decade ago; however, the process by which the signals are relayed from cell surface to nucleus is very complex with additional layers added in tumor cell niches. Although the intricate understanding of TGF-beta-mediated signaling pathways and their regulation are still evolving, we tried to make an attempt to summarize the TGF-beta-mediated SMAD-dependent andSMAD-independent pathways. This manuscript emphasizes the functions of TGF-beta as a metastatic promoter and tumor suppressor during the later and initial phases of tumor progression respectively.