Revisiting Metalloproteinases

Metalloproteinases

Among the molecules deployed by cells to interact with each other or the ECM, metalloproteinases have raised considerable interest. There are 24 matrix metalloproteinases (MMPs) known in the human genome. They may be secreted or present on the cell-surface as membrane-bound molecules.^[7] They bind and cleave a variety of substrates, in a zinc-dependent fashion.

Among the substrates, we find: structural proteins, proteases, building blocks of the ECM, inhibitors, clotting factors, growth factors, chemokines, cell surface receptors, and adhesion molecules.^[8,9] The list seems almost endless, but it gives a good hint as to how far reaching the effector and regulatory activities exerted by MMPs can be. Experience has shown that inflammatory cells, MMPs, and angiogenesis are causally linked both positively and negatively. Might this be the reason why the first results obtained in cancer studies in vivo with MMPs inhibitors have been so disappointing?^[2,3,4]

Since MMPs are expressed in almost all cancers and also in the macrophages, fibroblasts, and endothelial cells surrounding the tumors, they are critically situated to participate in extracellular signal transduction.^[10] Do they change cancer risk? Multiple and, at times, antagonistic functions have now been ascribed to MMPs in relation to cancer growth:^{[4,8,9,10,11]}

MMPs may enhance or block invasion by tumor cells;
MMPs can cleave e-cadherin and thus lead to scattering of cancer cells;
Cleavage of surface receptors leads to a more migratory pattern in cancer cells;
Cleavage of chemokines may, however, attenuate the gradients of migration-inducing factors.

Large-scale analysis of cancer-associated protein patterns (proteomics) is now being used to identify MMP substrates critically involved in cancer progression. Also, microarrays are being applied to reveal the extent of differential product expression in tumors vs normal tissues. More data and insights on the relative contribution of these factors to the development of cancer are expected in the future.

Cite this: Conference Report - Extracellular Matrix and Cancer: Revisiting Metalloproteinases - Medscape - Feb 24, 2004.

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