Membrane-type matrix metalloproteinases (MT-MMP)s: expression and functionduring glioma invasion

Membrane-type MMPs (MT-MMPs) constitute a growing subclass of recently iden tified matrix metalloproteinases (MMPs). In addition to the highly conserve d MMP functional domains, the MT-MMPs have additional insertion sequences ( IS) that confer unique functional roles. While most of the MMPs are secrete d, the MT-MMPs are membrane associated and a number of these have cytoplasm ic domains which may be important in cellular signaling. This membrane loca lization leads to focal areas of receptor recruitment and subsequent activi ty, thereby enhancing pericellular proteolysis in specific areas of contact within the brain interstitium. MT1-MMP is the best-characterized MT-MMP, t he measure against which subsequently cloned homologues are compared. MT1-M MP activates proMMP2 via its interaction with TIMP2, which serves as an int ermolecular bridge for proMMP2 binding to MT-MMPs. In addition to activatio n of proMMP2, MT-MMPs display intrinsic proteolytic activity towards extrac ellular matrix molecules (ECM), which is independent of MMP2 activation. Th e increased expression levels of several members of the MMP family have bee n shown to correlate with high-grade gliomas, including MT1-MMP. Despite im provements in the diagnosis and treatment of patients with glial tumors, th ey remain the most common and least curable brain cancer in adults. The abi lity of glioma cells to infiltrate surrounding brain tissue, and ultimately escape current therapeutic modalities, could potentially be minimized usin g anti-invasive therapies. Proteolysis is a necessary part of the invasion process, within which the MT-MMPs appear to play a central role. The develo pment of pharmaceutical approaches that target expression and regulation of MT-MMPs may prove beneficial in targeting invading glioma cells.