HUMAN BRAIN TUMOR INVASION

本项目的长期目标是确定 恶性神经胶质瘤侵袭大脑的可能性， 这种行为。 我们假设神经胶质瘤细胞具有局部侵袭性 因为调节细胞凋亡的基因表达发生了改变， 细胞与其细胞外环境之间的相互作用。 具体而言，本项目提出：1）比较正常和致瘤性 神经胶质细胞的组成和刺激生产的基质- 降解蛋白酶。 细胞条件培养基和膜组分 将研究来自对照和表皮生长因子刺激的细胞 使用底物凝胶电泳（酶谱）测定酶活性; 激活剂对蛋白水解活性的分泌后调节，或 将测量细胞上的抑制剂和蛋白酶受体。2)到 确定特异性基质蛋白的机制和程度， 影响胶质瘤细胞生长、迁移和侵袭。的表达 将研究胶质瘤细胞的特异性基质受体（整合素 使用功能测定并通过北方和西方印迹定量。 将通过测定细胞的定量，在体外测量侵袭性。 小鼠脑细胞的三维聚集体被 共培养期间和使用颅内异种移植物的体内胶质瘤细胞 在无胸腺小鼠中。3)以确定治疗的机制， 胶质瘤细胞与膜活性剂干扰的侵袭， 在体外和体内的脑。 我们的研究结果应该有助于 开发一种治疗性阻断神经胶质瘤细胞局部扩散的方法， 这可能会将神经胶质肿瘤转化为更容易切除的肿瘤 和/或使它们更易于通过辐射进行聚焦治疗。

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.