Invasion into brain parenchyma is an inherent feature of the malignant phenotype of glial neoplasms. The list of candidate invasion genes includes integrins, matrix remodeling enzymes (proteases), and other mediators of cell motility such as SPARC and BEHAB, which are well-characterized processes known to support migration or invasion of fetal cells, normal mature cells, as well as tumor cells. While it is anticipated that glioma invasion would exploit some normal genetic, molecular pathology specific to brain invasion transformed as been elucidated. Our success to date with laser capture microdissection of glioma cells from tumor core and invasive rim followed by mRNA differential display leads us to HYPOTHESIZE that local invasion by malignant glioma cells is driven by specific and unique gene expression changes. Interference with the expression of these genes or function of the gene products is likely to specifically target invasive glioma cells, consequently impacting a major source of tumor recurrence. This hypothesis will be tested by pursuing the following specific aims: 1. sustain the discovery of candidate genes expressed or silenced in highly invasive glioma cells compared to noninvading cells in the same tumor. We will use laser capture microdissection to retrieve from cryostat sections of human glioma specimens both invading cells and cells from the tumor core (non invading) and then employ differential display to identify genes uniquely expressed in these populations of cells. 2. test for clinical validation of the these genes in human glioma invasion. Clinical associations between glioma invasion and gene candidates will be tested by LCM collection of glioma cells from tumor core and invasive rim of biopsies, and subsequent quantitative RT-PCR for gene candidates identified from the differential display. And 3. determine the cellular and biochemical mechanisms of action of these genes. Specific inhibition or activation strategies (antibodies, antisense oligonucleotides, transfection of identified genes, and site-directed mutagenesis), and immunolocalization by confocal microscopy, co-immunoprecipitation with receptors and signaling molecules will be used to determine the function of the genes in glioma invasion. An improved understanding of genetic mechanisms underlying malignant glioma invasion will provide a more thorough repertoire of the molecular pathology of both gliomagenesis and glioma progression, as well as identify novel targets for therapeutic intervention.
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