Membrane-type matrix metalloproteinases (MT-MMPs): expression and function during glioma invasion.

Membrane-type MMPs (MT-MMPs) constitute a growing subclass of recently identified matrix metalloproteinases (MMPs). In addition to the highly conserved MMP functional domains, the MT-MMPs have additional insertion sequences (IS) that confer unique functional roles. While most of the MMPs are secreted, the MT-MMPs are membrane associated and a number of these have cytoplasmic domains which may be important in cellular signaling. This membrane localization leads to focal areas of receptor recruitment and subsequent activity, thereby enhancing pericellular proteolysis in specific areas of contact within the brain interstitium. MT1-MMP is the best-characterized MT-MMP, the measure against which subsequently cloned homologues are compared. MT1-MMP activates proMMP2 via its interaction with TIMP2, which serves as an intermolecular bridge for proMMP2 binding to MT-MMPs. In addition to activation of proMMP2, MT-MMPs display intrinsic proteolytic activity towards extracellular matrix molecules (ECM), which is independent of MMP2 activation. The increased expression levels of several members of the MMP family have been shown to correlate with high-grade gliomas, including MTI-MMP. Despite improvements in the diagnosis and treatment of patients with glial tumors, they remain the most common and least curable brain cancer in adults. The ability of glioma cells to infiltrate surrounding brain tissue, and ultimately escape current therapeutic modalities, could potentially be minimized using anti-invasive therapies. Proteolysis is a necessary part of the invasion process, within which the MT-MMPs appear to play a central role. The development of pharmaceutical approaches that target expression and regulation of MT-MMPs may prove beneficial in targeting invading glioma cells.

The role of matrix metalloproteinase genes in glioma invasion: co-dependent and interactive proteolysis.

Matrix metalloproteinases (MMPs) are cation-dependent endopeptidases which have been implicated in the malignancy of gliomas. It is thought that the MMPs play a critical role in both metastasis and angiogenesis, and that interference with proteases might therefore deter local tumor dissemination and neovascularization. However, the attempt to control tumor-associated proteolysis will rely on better definition of the normal tissue function of MMPs, an area of study still in its infancy in the central nervous system (CNS). Understanding the role of MMP-mediated proteolysis in the brain relies heavily on advances in other areas of molecular neuroscience, most notably an understanding of extracellular matrix (ECM) composition and the function of cell adhesion molecules such as integrins, which communicate knowledge of ECM composition intracellularly. Recently, protease expression and function has been shown to be strongly influenced by the functional state and signaling properties of integrins. Here we review MMP function and expression in gliomas and present examples of MMP profiling studies in glioma tissues and cell lines by RT-PCR and Western blotting. Co-expression of MMPs and certain integrins substantiates the gathering evidence of a functional intersection between the two, and inhibition studies using recombinant TIMP-1 and integrin antisera demonstrate significant inhibition of glioma invasion in vitro. Use of promising new therapeutic compounds with anti-MMP and anti-invasion effects are discussed. These data underline the importance of functional interaction of MMPs with accessory proteins such as integrins during invasion, and the need for further studies to elucidate the molecular underpinnings of this process.