MEMBRANE-TYPE METALLOPROTEINASES IN TUMOR INVASION

Matrix metalloproteinases (MMPs) are members of a multigene family of zinc-dependent enzymes involved in the degradation of numerous extrace llular matrix (ECM) components. Among these enzymes, membrane-type MMP s (MT-MMPs) play a major role in the activation of progelatinase A (MM P-2). The molecular structure of these enzymes is characterized by a t ransmembrane domain and the presence of an insertion of 11 amino-acids between the pro-peptide and the catalytic domains, which may be cleav ed by furin-like enzymes leading to the activated form of the enzymes. MT1-MMP appears to play a dual role in extracellular matrix remodelin g through activation of progelatinase A and procollagenase 3 and direc t cleavage of some ECM macromolecules such as gelatin, type I collagen and fibronectin. Tissue inhibitor of MMPs-2 (TIMP-2) serves as an int ermediate in progelatinase A activation by binding to MT1-MMP and prog elatinase A on the plasma membrane. In vivo, MT1-MMP is overexpressed in malignant tumor tissues in which it was mainly localized in stromal cells surrounding the neoplastic tissue. These peritumoral fibroblast s, under particular stimuli, would be induced to overexpress MT1-MMP a nd consequently activate gelatinase A leading to ECM degradation. The expression of MT1-MMP is however observed in vitro in the invasive tum or cells which might represent an late stage of tumor progression. All these data confirm the important role of MT-MMPs in tumor invasion an d highlight a cooperation between tumor and stromal cells for the prod uction of these enzymes. The contribution of MMPs in a metastatic proc ess leads to the development of novel therapies using inhibitors of th ese enzymes. Among a multitude of synthetic inhibitors generated, Mari mastat is already clinically employed in cancer treatment. (C) 1998 El sevier Science Ltd. All rights reserved.