TGF-I3 signaling pathway: Therapeutic targeting and potential for anti-cancer immunity

Transforming growth factor-I3 (TGFI3) is a pleiotropic secretory cytokine exhibiting both cancer-inhibitory and promoting properties. It transmits its signals via Suppressor of Mother against Decapentaplegic (SMAD) and nonSMAD pathways and regulates cell proliferation, differentiation, invasion, migration, and apoptosis. In noncancer and early-stage cancer cells, TGFI3 signaling suppresses cancer progression via inducing apoptosis, cell cycle arrest, or anti-proliferation, and promoting cell differentiation. On the other hand, TGFI3 may also act as an oncogene in advanced stages of tumors, wherein it develops immune-suppressive tumor microenvironments and induces the proliferation of cancer cells, invasion, angiogenesis, tumorigenesis, and metastasis. Higher TGFI3 expression leads to the instigation and development of cancer. Therefore, suppressing TGFI3 signals may present a potential treatment option for inhibiting tumorigenesis and metastasis. Different inhibitory molecules, including ligand traps, anti-sense oligo-nucleotides, small molecule receptor-kinase inhibitors, small molecule inhibitors, and vaccines, have been developed and clinically trialed for blocking the TGFI3 signaling pathway. These molecules are not pro-oncogenic response-specific but block all signaling effects induced by TGFI3. Nonetheless, targeting the activation of TGFI3 signaling with maximized specificity and minimized toxicity can enhance the efficacy of therapeutic approaches against this signaling pathway. The molecules that are used to target TGFI3 are non-cytotoxic to cancer cells but designed to curtail the over-activation of invasion and metastasis driving TGFI3 signaling in stromal and cancer cells. Here, we discussed the critical role of TGFI3 in tumorigenesis, and metastasis, as well as the outcome and the promising achievement of TGFI3 inhibitory molecules in the treatment of cancer.