Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development

Abstract

Matrix metalloproteinases (MMPs) were initially recognised for their extracellular matrix (ECM)-degrading capability during tissue remodelling. Their importance was further highlighted by their role in metastasis. Clinical trials have since evaluated the potential of MMP inhibitors as anticancer therapeutics, but without success. These initial studies point to the complex, multifunctional capacity of MMPs in cancer as shown by their function, not only as strident mediators of advanced malignancies, but also as effectors of early stage tumorigenesis. Research now shows that MMPs, and their tissue inhibitors, affect tumour initiation and growth through loss of cell adhesion, evasion of apoptosis, and deregulation of cell division. The extracellular nature of the metalloproteinase axis situates it as a master regulator of cell fate.

Efficacy of the MMP inhibitor MMI270 against lung metastasis following removal of orthotopically transplanted human colon cancer in rat

“…These additional functions mediated by MMPs include activation of growth factors, suppression of tumor cell apoptosis, destruction of chemokine gradients developed by host immune response or release of angiogenic factors. 9,10,25,26 Our results in MVD, PI, AI and in in vitro cell growth activity indicated that MMI270 had antiangiogenic activity, antiproliferative activity and activity of apoptosis induction through inhibition of MMPs activities in vivo. Of interest, these values were similar between Group A and Group C, although the survival rate and the inhibitory activity against lung metastasis in Group A were higher than those in Group C. One of the reasons for this result would be reactivation of tumor vascularization in Group A during the 2 weeks between the stop of MMI270 administration and the autopsy.…”

Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling

“…The proangiogenic protein MMP9 featured prominently in the analysis. MMP9 plays a critical role in the development of tumor-associated vasculature and can enhance the invasive potential of tumor cells (Pepper, 2001;Hojilla et al, 2003). Upregulation of this gene may be linked to increased levels of HMGA1 and TFAP2A, which are both positive regulators of MMP9 (Liu et al, 1999;Sivak et al, 2004).…”

Metalloproteinase inhibitor TIMP‐1 affects hepatocyte cell cycle via HGF activation in murine liver regeneration†

“…7 We have previously shown that TIMP-1 overexpression in the liver inhibits neoplastic hepatocyte proliferation by decreasing MMP-mediated release of insulin-like growth factor II from its binding proteins. 39,48 During liver regeneration, several molecules are possible candidates for MMP-mediated processing, including epidermal growth factor, transforming growth factor ␤, and fibroblast growth factor.…”

“…2,3 The rapid response to liver injury requires immediate release of multiple factors independent of de novo protein synthesis; a current hypothesis is that pericellular proteolytic events partici-pate in regulating hepatocyte division and reconstitution of cellular mass. 2 Metalloproteinases are now recognized for controlling both ECM remodeling and growth factor bioactivity, [5][6][7] yet little is known of their function in organ regeneration.…”