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。肿瘤胶质细胞的基因组图谱揭示了促使这些行为的每一种行为的失调的潜在基础。最近，将加速迁移与抑制增殖、诱导运动与减少凋亡联系在一起的功能关联要求更详细地研究这些不同的恶性表型特征相互影响的方式。这个项目的中心假设是，迁移受阻会促进恶性阴郁细胞的凋亡。其具体目的是：1)评估移行率与细胞死亡易感性之间的定量关系。黏附于迁移刺激的纯化的ECM蛋白、强迫过度表达或下调迁移诱导蛋白、药物或免疫调节细胞表面受体或调节迁移的信号转导通路将调节SLOW细胞的迁移速度。将评估临床上有用的药物对诱导细胞凋亡的影响。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)检测胶质瘤细胞迁移受阻是否促进体内细胞死亡的激活。来自特定目标1的结果将用于识别可促进诱导细胞死亡的靶点。胶质瘤异种移植模型将被用来评估迁移抑制因子在细胞毒剂诱导体内细胞死亡中的作用。在其对NINDS的优先事项和计划的描述(最近发表于1999年8月)中，神经环境专题组指出：“一个目标是对当这种肿瘤(胶质瘤)发生时激活的所有基因进行排序，以便了解是什么导致肿瘤细胞不受控制的增殖和对周围脑组织的侵袭。”在NCI和NINDS共同发起的最近一份关于脑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。根据R21计划指南的一致要求，本项目概述了新技术的发展，重点是如何发现和利用抗迁移或抗侵袭策略，以加强对胶质细胞肿瘤的细胞毒治疗的干预。

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.