TGF-beta as a key to glioma invasion

描述(由申请人提供)： 侵袭性生长是星形细胞瘤的一个特征，也是高级别肿瘤预后不佳的关键因素。此R21应用程序旨在从诊断时起阻止星形细胞瘤的侵袭。这一目标是对我们长期努力的补充，目的是将迁移性T细胞引导到已经侵袭的星形细胞瘤。这个R21项目将使我们能够获得全面支持R01所需的初步数据。两个目标将同时实现。目的1.验证转化生长因子-β1(TGF-β1)是脑瘤侵袭的关键调节因子的假说。目的2.验证在其他情况下影响转化生长因子-β1并减少侵袭的药物也可以减少脑瘤体内侵袭的假说。我们将在这里测试的特殊药物是抗纤维化/抗炎药物吡非尼酮。在这个修改后的应用中，我们使用了各种动物模型，适合测试肿瘤在大脑中的不同侵袭途径。我们包括我们实验室已经在积极使用的大鼠胶质瘤来源的细胞系；我们最近开发的脑转移乳腺癌模型；以及一组表达不同水平的转化生长因子-β1的小鼠星形细胞瘤克隆，它们可能比大多数啮齿类胶质瘤细胞系更好地模拟单细胞侵袭。方法包括组织培养、细胞生长分析、免疫组织化学、肿瘤细胞系立体定向移植、荷瘤小鼠和大鼠的药物治疗。 将使用老鼠和大鼠。

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.