PTP mu Supresses Brain Tumor Cell Migration and Dispersal

被称为胶质瘤的中枢神经系统肿瘤是一个重大的健康问题，他们的 由于缺乏有效的筛查或治疗，预后很差。胶质瘤的主要治疗方法是 手术和放射治疗。侵袭性原发肿瘤的外科切除受限于肿瘤向 正常的大脑。放射治疗的效果有限。因此，必须开发新的化疗策略来 有效地治疗这些神经胶质瘤。原发脑瘤很少转移到其他器官，但大多数 侵袭性肿瘤通常广泛分散，并在整个中枢神经系统广泛扩散。 这种扩散和扩散是如何调控的尚不清楚，但很可能关键取决于相互作用。 肿瘤细胞和大脑环境之间的关系。识别控制的关键调控信号 细胞通讯和迁移将使治疗胶质瘤的新疗法的发展成为可能。细胞 黏附分子是黏附依赖信号的重要调节者，如接触抑制 成长和运动。PTPu是一种细胞表面受体蛋白酪氨酸磷酸酶(RPTP)，是 在神经胶质细胞中表达。PTPu是一种嗜同型细胞黏附分子，可调节钙粘附素- 依附附着力。在初步研究中，我们确定PTPu蛋白的表达下调 在不同类型的人脑胶质瘤中。我们的假设是，PTPu可能直接转导细胞内信号 对控制神经胶质细胞迁移的细胞黏附作出反应。与这一假设相一致，最初 研究表明，PTPjj在高度分散的人脑胶质瘤细胞系中的重新表达抑制了肿瘤细胞的迁移 一种利用老鼠脑进行的入侵试验。此外，PTPu在非侵袭性组织中的表达下调 胶质瘤细胞系现在导致这些细胞在脑片侵袭试验中迁移。这些数据表明 PTPu在胶质瘤转移的关键事件中的作用，并形成了拟议研究的基础。具体目标是： I.分析PTPu在不同类型人脑原发肿瘤中的表达 II.改变PTPu在胶质瘤细胞中的表达和催化活性，并检测其迁移和侵袭 确定PTP|j负性调节细胞迁移和 人脑胶质瘤细胞的侵袭性

Tumors of the central nervous system known as gliomas represent a significant health concern and their prognosis is poor due to the lack of effective screening or therapies. The main treatments for glioma are surgery and radiation. Surgical resection of aggressive primary tumors is limited by tumor infiltration into normal brain. Radiation has limited efficacy. Thus, novel chemotherapeutic strategies must be developed to effectively treat these gliomas. Primary brain tumors rarely metastasize to other organs but the most aggressive tumors often disperse widely, and proliferate extensively throughout the central nervous system. How this dispersal and proliferation is regulated is unclear, but is likely to depend critically on interactions between the tumor cell and the environment of the brain. Identification of key regulatory signals that control cellular communication and migration will allow development of novel therapeutics to treat gliomas. Cell adhesion molecules are important regulators of adhesion-dependent signals such as contact inhibition of growth and movement. PTPu is a cell surface receptor protein tyrosine phosphatase (RPTP) that is expressed in glial cells. PTPu is a homophilic cell adhesion molecule that is known to regulate cadherin- dependent adhesion. In preliminary studies, we determined that PTPu protein expression is down-regulated in distinct types of human gliomas. Our hypothesis is that PTPu may directly transduce intracellular signals in response to cell adhesion that control migration of glial cells. Consistent with this hypothesis, initial studies suggest that re-expression of PTPjj in a highly dispersive human glioma cell line inhibits migration in an invasion assay using rat brains. In addition, down-regulation of PTPu expression in a non-invasive glioma cell line now causes these cells to migrate in the brain slice invasion assay. These data implicate PTPu in critical events in glioma migration and form the basis for the proposed study. The specific aims are: I. Analyze PTPu expression in different types of human primary brain tumors II. Alter PTPu expression and catalytic activity in glioma cells and examine migration and invasion III. Determine the molecular mechanisms by which PTP|j negatively regulates cell migration and invasion in glioma cells