Activation of transforming growth factor beta 1 through integrin alpha V beta 6 and its molecular insights into cancer progression, and future directions.

Cancer metastasis is the last stage of cancer and can often lead to lethality. Cancer cells invade distal organs and establish an entirely new host microenvironment. Among several cancer-influencing mediators, TGF-β has been observed as a potential pro-oncogene to provoke metastasis. Among the 3 isoforms of TGF-β, TGF-β1 is identified as a strong promoter of several cancers, including colorectal, lung, gastric, and prostate cancer. TGF-β1 is always made by cells as an inactive, latent complex, which must be activated to function. A crucial activator of TGF-β is integrin αVβ6, which has a strong association with tumor development. Due to the pivotal role of integrin αVβ6 in activating latent-TGF-β1, and subsequent modulation of downstream signaling cascades as well as cell adhesion, the integrin emerges as a prime target for the development of anti-cancer drugs. However, MMP-9 is also activated by integrin αVβ6 to induce the EMT process. Nevertheless, other proteins, including thrombospondins-1 and ADAMTS proteases 1, may potentially activate latent-TGF-β1. This review summarizes our knowledge of TGF-β1 activation, especially by integrin αVβ6, as well as other proteins, focusing on the structural aspects of this process. Importantly, this review also elucidated the function of amino acids that may be involved in the interaction between latent-TGF-β1 and integrin αVβ6, as these amino acid sequences aids in the development of treatments targeting the progression of cancer mediated by TGF-β1 and integrin αVβ6.