Malignant gliomas represent one of the most refractory cancers to therapy and remain incurable. Brain invasiveness by gliomas is one of the main reasons for failure of surgical therapy because of the inability to accomplish a complete resection. Tissue invasiveness by a tumor depends in great part on the appropriate proteolytic enzymes necessary to overcome the various barriers to its progression. It is our hypothesis that plasminogen activators (PAs) and collagenases are intimately involved in glioma invasiveness and that the overall proteolytic activity is dependent on the presence of specific inhibitors, on the constitution of the extra-cellular matrix, and on the more recently recognized role of urokinase receptor in tissue invasiveness. In this proposal we plan to study the invasiveness of several glioblastoma cell lines using in vitro and in vivo models. We will estimate the levels of PAs, PA inhibitors, collagenases their inhibitors (TIMPs) produced by the cell lines in cell culture (in vitro) and by tumors growing intracranially in nude mice (in vivo) using biochemical and immunohistochemical assays. Immunohistochemical assays will be required to identify the cellular source of the enzyme or the inhibitor under study. In addition, the ability of the cell lines to degrade specific extracellular matrix (ECM) components, present in normal brain or produced by the cell lines, will be tested in vitro. Together, these studies should provide important insights in the role of proteases and their inhibitors in promoting glial tumor invasiveness with the hope of providing new avenues for therapeutic interventions.
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