Can Brain Specific Matrix Mediate Glioma Invasion?

描述(申请人提供)：中枢神经原发肿瘤 众所周知，神经胶质瘤很难控制，这在很大程度上是由于 他们的高度侵犯性行为。细胞在组织中迁移的能力 部分取决于组织细胞外基质(ECM)的组成。 了解细胞外环境的分子组成 脑肿瘤是开发预防肿瘤侵袭的方法之一。 BEHAB/brevican，一种最近发现的大脑特异性ECM蛋白，显著地 在人脑胶质瘤和脑胶质瘤实验模型中表达上调。在人类中 人脑胶质瘤中BEHAB/Brivican的表达比正常成人高700% 在任何非神经胶质来源的肿瘤中都没有检测到人脑和表达，甚至 当这些肿瘤在大脑中生长时。 我们在上一个资助期的工作提供了证据 BEHAB/Brivican在脑胶质瘤侵袭中起作用。这里提出的实验 将检验这一假说，此外，还将检验 BEHAB/Brivican可能为脑胶质瘤提供新的治疗靶点。在……里面 实验性脑胶质瘤细胞模型中BEHAB/Brivican的表达 大脑特有的因素。此应用程序的第一个特定目标是 BEHAB/Brivican诱导机制的表征及鉴定 潜在的诱发因素。几条趋同的证据表明 BEHAB/Brivican在胶质瘤中的功能需要蛋白降解处理 入侵。本应用程序第二个特定目标是将 BEHAB/Brivican在胶质瘤中的裂解作用减缓或预防胶质瘤 细胞运动可以提高区域疗法的疗效；第三 此应用程序的特定目的是确定抑制剂是否 BEHAB/Brivican切割可以减缓肿瘤的侵袭，因此可能提供一种 治疗胶质瘤的新途径。我们的工作导致了这样的假设 BEHAB/Brivican的生产、切割和周转共同调节细胞外基质 并能调节细胞的运动。我们的最终具体目标是测试一个角色 BEHAB/Brivican转换在胶质瘤侵袭中的作用我们的长期目标是确定 如果BEHAB的功能减少或消除可以延缓 原发脑瘤。

DESCRIPTION (provided by applicant): Primary tumors of the central nervous system, gliomas, are notoriously difficult to control, due in large measure to their highly invasive behavior. The ability of cells to migrate through tissue depends, in part, on the composition of the tissues extracellular matrix (ECM). Understanding the molecular composition of the extracellular environment of brain tumors is one approach to developing methods to prevent tumor invasion. BEHAB/brevican, a recently identified brain-specific ECM protein, is markedly upregulated in human glioma and in experimental models of glioma. In human glioma BEHAB/brevican expression is 700 percent over that in the normal adult human brain and expression is not detected in any non-glial derived tumor, even when these tumors grow within the brain. Our work during the previous funding period has provided evidence that BEHAB/brevican plays a role in glioma invasion. The experiments proposed here will test this hypothesis and, in addition, will test the possibility that BEHAB/brevican may provide a novel therapeutic target for glioma. In experimental glioma cel models, BEHAB/brevican expression is induced by a brain-specific factor. The first specific aim of this application is to characterize the mechanism of BEHAB/brevican induction and to identify potential inducing factors. Several converging lines of evidence suggest that proteolytic processing is required for BEHAB/brevican function in glioma invasion. The second specific aim of this application is to characterize BEHAB/brevican Droteolytic cleava2e in glioma. Slowing or preventing glioma cell motility could increase the efficacy of regional therapies; the third specific aim of this application is to determine whether inhibitors of BEHAB/brevican cleavage can slow tumor invasion and, therefore, might provide a new therapeutic avenue foi glioma. Our work has led to the hypothesis that production, cleavage, and turnover of BEHAB/brevican together modulate the ECM and can regulate cell motility. Our final specific aim is to test a role for BEHAB/brevican turnover in glioma invasion. Our long-term goal is to determine if functional reduction or elimination of BEHAB could slow the progression of primary brain tumor.