title: The role of matrix metalloproteinase genes in glioma invasion: co-dependent and interactive proteolysis.
abstract: 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.
authors.affiliation: Department of Neuropathology, Institute of Psychiatry, King's College London, De Crespigny Park, London, UK.
authors.forename: T E
authors.initials: TE
authors.lastname: VanMeter
authors.forename: H K
authors.initials: HK
authors.lastname: Rooprai
authors.forename: M M
authors.initials: MM
authors.lastname: Kibble
authors.forename: H L
authors.initials: HL
authors.lastname: Fillmore
authors.forename: W C
authors.initials: WC
authors.lastname: Broaddus
authors.forename: G J
authors.initials: GJ
authors.lastname: Pilkington
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D002462:Cell Membrane / Q000201:enzymology; D022081:Cell Surface Extensions / Q000201:enzymology; D003599:Cytoskeleton / Q000187:drug effects; D018450:Disease Progression; D015195:Drug Design; D004790:Enzyme Induction; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007106:Immune Sera; D016023:Integrins / Q000037:antagonists & inhibitors / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D008666:Metalloendopeptidases / Q000145:classification / Q000235:genetics / Q000502:physiology*; D051379:Mice; D015394:Molecular Structure; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D017978:Receptors, Growth Factor / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology / Q000502:physiology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D016326:Extracellular Matrix Proteins; D007106:Immune Sera; D016023:Integrins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017978:Receptors, Growth Factor; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases