| Abstract: | One important proteolytic event during metastasis and angiogenesis appears to be the degradation of basement membrane components. A specific class of extracellular matrix (ECM) degrading metallo-enzymes, the matrix metalloproteinases (MMPs), also known as the matrixins, are thought to have a critical role in the creation of the proteolytic defect in basement membrane type IV collagen that allows tumour cells to escape from their primary site. The expression of matrixin proteases has been linked with many physiologic and pathologic processes involving ECM turnover. A number of correlative and functional studies suggest that the action of MMPs is required during tumour invasion and progression, as well as angiogenesis. The correlative studies have demonstrated overexpression of MMPs in many human cancer tissues at both the protein (immunoperoxidase) and mRNA (in situ hybridisation) levels. Functional studies have used endogenous inhibitors (Tissue Inhibitors of Metalloproteinases, TIMPs) or synthetic MMP inhibitors to block tumour cell invasion or metastasis formation. MMPs have also been implicated in the cell-surface proteolysis that modulates the adhesive behaviour of neoplastic cells. Therefore, targeting the activity of MMPs may provide a clinically useful mechanism for blocking local invasion and the metastatic spread of cancer cells. Results from a variety of studies indicate that mechanism-based inhibitors for MMPs can be developed and exploited in the clinical setting. This strategy has been utilised for the development of MMP inhibitors as substrate analogues have been modified to target selectively reactive moieties at the active site of MMPs. |
