PTP mu Supresses Brain Tumor Cell Migration and Dispersal

被称为神经胶质瘤的中枢神经系统肿瘤代表了一个重大的健康问题，并且其 由于缺乏有效的筛查或治疗，预后很差。神经胶质瘤的主要治疗方法是 手术和放疗侵袭性原发性肿瘤的手术切除受限于肿瘤浸润到 正常的大脑辐射的效果有限。因此，必须开发新的化疗策略， 有效治疗这些神经胶质瘤原发性脑肿瘤很少转移到其他器官， 侵袭性肿瘤通常广泛分散，并在整个中枢神经系统中广泛增殖。 这种扩散和增殖是如何调节的尚不清楚，但很可能主要取决于相互作用 肿瘤细胞和大脑环境之间的联系。识别控制的关键调控信号 细胞通讯和迁移将允许开发治疗神经胶质瘤的新疗法。细胞 粘附分子是粘附依赖性信号的重要调节剂，例如粘附分子的接触抑制。 生长和运动。PTPu是一种细胞表面受体蛋白酪氨酸磷酸酶（RPTP）， 在神经胶质细胞中表达。PTPu是一种嗜同性细胞粘附分子，已知其调节钙粘蛋白- 依赖性粘附在初步研究中，我们确定PTPu蛋白表达下调， 不同类型的人类神经胶质瘤。我们的假设是PTPu可能直接干扰细胞内信号 响应于控制神经胶质细胞迁移细胞粘附。根据这一假设， 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神经胶质瘤细胞的迁移， 一个用老鼠大脑做的入侵实验。此外，PTPu表达的下调，在一个非侵入性的， 神经胶质瘤细胞系现在在脑切片侵袭测定中引起这些细胞迁移。这些数据表明 PTPu在胶质瘤迁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在不同类型原发性脑肿瘤中的表达 二.改变胶质瘤细胞PTPu的表达和催化活性并检测其迁移和侵袭 三.确定PTP的分子机制|j负调节细胞迁移， 胶质瘤细胞侵袭

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