Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.

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Matrix metalloproteinases and the regulation of tissue remodelling

Tissue inhibitors of metalloproteinases: evolution, structure and function.

Functions of individual matrix metalloproteinases (MMPs) differentially expressed by tumor cells and stromal cells, are finely regulated by their spatial as well as temporal interactions with distinct cellular and extracellular components of the tumor microenvironment and also distant pre-metastatic sites. Certain aspects of MMP involvement in tumor metastasis such as tumor-induced angiogenesis, tumor invasion, and establishment of metastatic foci at the secondary site, have received extensive attention that resulted in an overwhelming amount of experimental and observational data in favor of critical roles of MMPs in these processes. In particular, dependency of tumor angiogenesis on the activity of MMPs, especially that of MMP-9, renders this step possibly the most effective target of synthetic MMP inhibitors. MMP functioning in other stages of metastasis, including the escape of individual tumor cells from the primary tumor, their intravasation, survival in circulation, and extravasation at the secondary site, have not yet received enough consideration, resulting in insufficient or controversial data. The major pieces of evidence that are most compelling and clearly determine the role and involvement of MMPs in the metastatic cascade are provided by molecular genetic studies employing knock-out or transgenic animals and tumor cell lines, modified to overexpress or downregulate a specific MMP. Findings from all of these studies implicate different functional mechanisms for both tumor and stromal MMPs during distinct steps of the metastatic cascade and indicate that MMPs can exhibit pro-metastatic as well as anti-metastatic roles depending on their nature and the experimental setting. This dual function of individual MMPs in metastasis has become a major focus of this review.

Matrix metalloproteinases and tumor metastasis

Mechanism Of Cell Surface Activation Of 72-kDa Type IV Collagenase ISOLATION OF THE ACTIVATED FORM OF THE MEMBRANE METALLOPROTEASE

Localization of Matrix Metalloproteinase MMP-2 to the Surface of Invasive Cells by Interaction with Integrin αvβ3

GELATINASE A (type-IV collagenase; Mr 72,000) is produced by tumour stroma cells and is believed to be crucial for their invasion and metastasis, acting by degrading extracellular matrix macro-molecules such as type IV collagen1–3. An inactive precursor of gelatinase A (pro-gelatinase A) is secreted and activated in invasive tumour tissue4–7 as a result of proteolysis which is mediated by a fraction of tumour cell membrane that is sensitive to metallopro-teinase inhibitors4,5. Here we report the cloning of the complemen-tary DNA encoding a new matrix metalloproteinase with a potential transmembrane domain. Expression of the gene product on the cell surface induces specific activation of pro-gelatinase A in vitro and enhances cellular invasion of the reconstituted basement membrane. Tumour cells of invasive lung carcinomas, which con-tain activated forms of gelatinase A, were found to express the transcript and the gene product. The new metalloproteinase may thus trigger invasion by tumour cells by activating pro-gelatinase A on the tumour cell surface.

Jian Cao

Papers

A matrix metalloproteinase expressed on the surface of invasive tumour cells

The C-terminal Region of Membrane Type Matrix Metalloproteinase Is a Functional Transmembrane Domain Required for Pro-gelatinase A Activation