PTP mu Supresses Brain Tumor Cell Migration and Dispersal

描述(申请人提供)：中枢神经系统肿瘤，称为胶质瘤，是一个严重的健康问题，由于缺乏有效的筛查或治疗，其预后很差。胶质瘤的主要治疗方法是手术和放射治疗。侵袭性原发肿瘤的手术切除受限于肿瘤对正常脑组织的浸润性。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胶质瘤。原发性脑肿瘤很少转移到其他器官，但最具侵袭性的肿瘤通常广泛分散，并广泛扩散到整个中枢神经系统。这种扩散和增殖是如何调控的尚不清楚，但很可能关键取决于肿瘤细胞和大脑环境之间的相互作用。识别控制细胞通讯和迁移的关键调控信号将有助于开发治疗胶质瘤的新疗法。细胞黏附分子是黏附依赖信号的重要调节者，如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)，表达于神经胶质细胞。PTPu是一种亲水性细胞黏附分子，可调节钙粘附素依赖的黏附。在初步研究中，我们确定PTPu蛋白在不同类型的人脑胶质瘤中表达下调。我们的假设是，PTPu可能直接转导细胞内信号，以响应控制神经胶质细胞迁移的细胞黏附。与这一假设一致，初步研究表明，PTPjj在高度分散的人类胶质瘤细胞系中的重新表达在大鼠脑侵袭实验中抑制了迁移。此外，PTPu在非侵袭性胶质瘤细胞系中的表达下调现在导致这些细胞在脑片侵袭试验中迁移。这一数据表明PTPu参与了胶质瘤转移的关键事件，并形成了拟议研究的基础。具体目的是：1.分析PTPu在不同类型的人原发脑肿瘤中的表达。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能力。确定PTP|j负性调节胶质瘤细胞迁移和侵袭的分子机制。

DESCRIPTION (provided by applicant): 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. This data implicates 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.