Smriti Kanangat
Carcinogenesis is fundamentally the result of abnormalities in cell division functions, leading to unabated proliferation of cells. The key to finding a “cure” for all forms of cancer is to understand the fundamental genetic mechanisms of lack of cell cycle control, and to understand the genetics of immune response (how tumor escapes the immune surveillance) towards cancer cells so that one can start developing effective immune-based therapeutics such as the currently popular immune-checkpoint therapeutics. This review focuses on the role of Transforming Growth Factor-Beta (TGF-β) signaling pathways in molecular pathogenesis is of cancer along with possibility of finding novel biomarkers and targets for novel therapeutics. TGF-β is a versatile cytokine and it is a key player in normal development as well as Tumor development. It is a pleotropic cytokine with varied effects on varied cells and certainly has influence on cellular transformation (such as epithelial to mesenchymal transition) invasion, regulation of immune responses (such as T cell responses, and microenvironment modification that cancer cells may exploit to dislodge and migrate (metastasize). Hence, the TGF-β response is pertinent with respect to development and normal functions of the body and also in modulating carcinogenesis. Hence, unravelling the effects of TGF-β signaling pathway could lead to the in-depth understanding of its basic molecular role in triggering or transforming normal cells to cancerous cells directly or indirectly. Deciphering the molecular mechanisms of TGF-β based initiation process of carcinogenesis could help us to find novel targets for future more effective therapeutic intervention before the tumor becomes established and or metastasized. In the context on the role of TGF-β and carcinogenesis, Follistatin-like 3 (FSTL3) plays an important role. Because FSTL3 binds and inactivates Activin A, a member of the TGF family of proteins. Activin A has high levels of expression in breast cancer cells. Breast cancer cells have been shown to become insensitive to the growth-inhibiting action of Activin. This loss of sensitivity is caused partly by the expression of follistatin, and follistatin-related genes (FLRG) such as FSTL3, which bind to Activin A with high affinity thereby inhibiting Activin A’s growth inhibiting function. Although FSTL3 expression levels are varied in human tumors, previous studies have shown that there is an increased presence of FSTL3 in invasive breast cancer tumors. However, it’s not known yet whether the FSTL3 expression levels in breast cancer tumors correlate with and are causal to tumor growth and metastasis. Structurally, FSTL3 binds with much stronger affinity to Activin A than to other TGF-β superfamily ligands because of the strong interaction of the N-terminus of the FSTL3 protein with Activin A. So what essentially we are addressing in this issue is if FSTL3 could be a desired biomarker in breast cancer along with other downstream molecules associated with TGF and cell cycle events.