TGF-β and MMPs: A complex regulatory loop involved in tumor progression

Abstract

Transforming growth factor-β (TGF-β) has a dual and contradictory role in cancer. It is a tumor suppressor at early stages of tumor formation by virtue of its growth inhibitory and pro-apoptotic functions. However, at later stages of tumor progression, tumor cells lose their sensitivity to be growth inhibited by this cytokine, and, then, TGF-β facilitates tumor invasion and metastasis by diverse mechanisms, including the induction of an epithelial-mesenchymal transition, the suppression of the immune system and the stimulation of angiogenesis. Matrix metalloproteinases (MMPs) have also been shown to play a pivotal function in tumor cell migration, invasion and angiogenesis. MMPs and TGF-β form an interplay loop that may attenuate or promote tumor progression. On one hand, latent TGF-β, an inactive TGF-β precursor that is sequestered by the extracellular matrix, is proteolytically activated by MMPs; the released active cytokine may, then, suppress or promote tumor cell growth and invasiveness depending on the tumor stage. On the other hand, TGF-β regulates the expression of MMPs and their tissue inhibitors TIMPs in both tumor and stromal cells. MMPs in the tumor microenvironment are involved in the control of tumor cell growth and survival by modulating the bioavailability of growth factors and chemokines, and they also influence inflammation and angiogenesis. Thus, by modulating the net balance of MMPs and TIMPs in both compartments: the tumor and stroma, TGF-β regulates malignant progression.