The long term objectives of this project are to determine the mechanisms of malignant glioma invasion in the brain and to devise a means to block this behavior. We hypothesize that glioma cells are locally invasive because of alterations in the expression of genes which regulate interactions between cells and their extracellular environment. Specifically, this project proposes: 1) to compare normal and tumorigenic glial cells for their constitutive and stimulated production of matrix-- degrading proteinases. Cell-conditioned medium and membrane fractions from control and epidermal growth factor-stimulated cells will be studied for enzymatic activity using substrate gel electrophoresis (zymograms); post-secretory regulation of proteolytic activity by activators or inhibitors and proteinase receptors on the cells will be measured. 2) to determine the mechanisms and extent to which specific-matrix proteins influence glioma cell growth, migration and invasion. The expression of specific matrix receptors (integrins) by glioma cells will be studied using functional assays and quantified by northern and western blots. Invasiveness will be measured in vitro by determining the quantitative replacement of three dimensional aggregates of murine brain cells by glioma cells during coculture, and in vivo using intracranial xenografts in athymic mice. 3) to determine the mechanism by which treatment of glioma cells with membrane active agents interferes with invasion of brain in vitro and in vivo. The results from our studies should help to develop a means to therapeutically block the local spread of glioma cells which may convert glial neoplasms into more readily resectable tumors and/or render them more amenable to focal treatment by radiation.
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