TGF-beta as a key to glioma invasion

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DESCRIPTION (provided by applicant): Invasive growth is a hallmark of astrocytoma, and a key factor in the grim prognosis for high grade tumors. This R21 application aims to block astrocytoma invasion from the time of diagnosis. This aim complements our long-standing efforts to direct migratory T cells to astrocytoma that has already invaded. This R21 project will allow us to obtain the preliminary data needed for full-scale R01 support. Two AIMS will be carried out in parallel. AIM 1. Test the hypothesis that transforming growth factor-beta 1 (TGF-beta1) is a key regulator of brain tumor invasion. AIM 2. Test the hypothesis that pharmacologic agents which affect TGF-beta1 and reduce invasion in other contexts can also reduce brain tumor invasion in vivo. The particular agent we will test here is the anti-fibrotic/anti-inflammatory drug, pirfenidone. In this amended application, we use a variety of animal models, appropriate to testing different paths of tumor invasion in the brain. We include rat glioma-derived cell lines already in active use in our laboratory; a model for brain-metastasizing breast cancer, which we have recently developed; as well as a panel of murine astrocytoma clones made to express different levels of TGF-beta1, and which may be a better mimic of single cell invasion than most rodent glioma cell lines. Methods include tissue culture, cell growth assays, immunohistochemistry, stereotactic implantation of tumor cell lines, pharmacologic treatment of tumor-bearing mice and rats. Mice and rats will be used.