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 M MPs play a critical role in both metastasis and angiogenesis, and that inte rference with proteases might therefore deter local tumor dissemination and neovascularization. However, the attempt to control tumor-associated prote olysis 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 he avily on advances in other areas of molecular neuroscience, most notably an understanding of extracellular matrix (ECM) composition and the function o f cell adhesion molecules such as integrins, which communicate knowledge of ECM composition intracellularly. Recently, protease expression and functio n has been shown to be strongly influenced by the functional state and sign aling properties of integrins. Here we review MMP function and expression i n gliomas and present examples of MMP profiling studies in glioma tissues a nd cell lines by RT-PCR and Western blotting. Co-expression of MMPs and cer tain integrins substantiates the gathering evidence of a functional interse ction 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-in vasion effects are discussed. These data underline the importance of functi onal interaction of MMPs with accessory proteins such as integrins during i nvasion, and the need for further studies to elucidate the molecular underp innings of this process.