Arrested migration fosters apoptosis of glioma cells

描述（由申请人提供）： 胶质瘤细胞的恶性行为包括不受控制的增殖、实质侵袭和凋亡途径的可及性或活性降低。肿瘤性神经胶质细胞的基因组分析提供了对促进这些行为的失调的潜在基础的洞察。最近，功能协会连接加速迁移与抑制增殖，诱导运动与减少凋亡主张更详细的研究方式，这些不同的功能恶性表型相互影响。该项目的中心假设是，停滞的迁移促进恶性肿瘤细胞的凋亡。具体目的是：1）评估迁移速率与细胞死亡敏感性之间的定量关系。暗细胞的迁移速率将通过粘附于迁移刺激纯化的ECM蛋白、迁移诱导蛋白的被迫过表达或下调以及调节迁移的细胞表面受体或信号转导途径的药理学或免疫学操作来调节。将评估临床上有用的药物对细胞凋亡诱导的影响。将使用多个细胞系和原代胶质母细胞瘤外植体来确定这是否是胶质瘤细胞中的普遍现象。2)测试胶质瘤细胞的停滞迁移是否导致体内细胞死亡的促进激活。特异性目标1的结果将用于鉴定可促进诱导细胞死亡的靶点。神经胶质瘤肿瘤的异种移植模型将用于评估迁移抑制剂对细胞毒性剂在体内诱导细胞死亡的影响。在NINDS的优先事项和计划的描述中（最近于1999年8月出版），神经环境集群指出：“目标是对肿瘤（胶质瘤）出现时激活的所有基因进行测序，以了解是什么导致肿瘤细胞不受控制地增殖和侵入周围脑组织。“在最近由NCI和NINDS共同赞助的关于脑肿瘤的进展审查小组报告中，重申了改进发现胶质瘤侵袭机制的必要性。R21计划指南的一致要求，该项目概述了新技术的开发，重点是如何发现和利用抗迁移或抗侵袭策略作为增强干预措施，以改善针对神经胶质细胞肿瘤的细胞毒性治疗。

DESCRIPTION (provided by applicant): The malignant behavior of glioma cells involves uncontrolled proliferation, parenchymal invasion, and diminished accessibility or activity of apoptosis pathways. Genomic profiling of neoplastic glial cells gives insight into the underlying basis for the dysregulation prompting each of these behaviors. Recently, functional associations linking accelerated migration with suppressed proliferation, and induced motility with diminished apoptosis argue for more detailed study of ways in which these distinct features of the malignant phenotype impact one another. The central hypothesis of this project is that arrested migration fosters apoptosis of malignant gloom cells. The Specific Aims are: 1) Assess the quantitative relationship between rate of migration and susceptibility to cell death. The migration rate of gloom cells will modulated by adherence to migration stimulating purified ECM proteins, forced over expression or down regulation of migration inducing proteins and pharmacological or immunological manipulation of cell surface receptor or signal transduction pathways modulating migration. Effects on apoptosis induction by clinically useful agents will be assessed. Multiple cell lines and primary glioblastoma explants will be used to determine if this is a universal phenomenon among glioma cells. 2) Test whether arrested migration of glioma cells leads to facilitated activation of cell death in vivo. Results from Specific Aim 1 will be used to identify targets to manipulate that will facilitate induction of cell death. Xenograft models of glioma tumors will be used to assess effects of migration suppressors on induction of cell death in vivo by cytotoxic agents. In its description of Priorities and Plans for the NINDS (published most recently in August, 1999), the Neural Environment cluster states that "A goal is to sequence all genes activated when this tumor (glioma) arises in order to understand what causes uncontrolled tumor cell proliferation and invasion of surrounding brain tissue." The need for improved discovery of mechanisms of glioma invasion was reiterated in recent Progress Review Group report on Brain Tumors, co-sponsored by the NCI and the NINDS. Consistent requirements of the R21 Program Guidelines, this project outlines development of novel technologies focused on ways to discover and exploit anti-migratory or anti-invasive strategies as potentiating interventions for improving cytotoxic therapy against glial cell tumors.