Mechanisms of glioma growth and invasion novel therapeutic strategies

描述（由申请人提供）：高级别胶质瘤具有均匀致死性，对手术、化疗和放疗具有耐药性。神经胶质瘤细胞在大脑中扩散并生长形成宏观症状性肿瘤的确切细胞和分子机制尚不清楚。在此，我们建议测试有关胶质瘤生长的新的细胞，分子和机制假设，以及如何将这些知识转化为新的抗胶质瘤治疗方法。我的实验室使用共聚焦、电子和多光子显微镜进行的初步工作表明，胶质瘤细胞和人类胶质瘤干细胞在体内通过优先沿着血管周围腔室（一个围绕大脑微血管的潜在迁移网络）在大脑中分散。当神经胶质瘤细胞在血管周围网络中移动时，它们将神经胶质端足从血管中移除，并损害邻近的脑组织；这些细胞随后被肿瘤细胞所取代。我们还获得了初步数据，表明一种聚糖结合蛋白半乳糖凝集素-1对这种生长机制至关重要。

DESCRIPTION (provided by applicant): High grade gliomas are uniformly lethal, and resistant to surgery, chemotherapy and radiotherapy. The precise cellular and molecular mechanisms by which glioma cells disperse through the brain and grow to form macroscopic symptomatic tumor masses remains poorly understood. Herein we propose to test novel cellular, molecular and mechanistic hypotheses concerning glioma growth, and how to translate this knowledge into new anti-glioma therapeutics. Preliminary work from my laboratory, using confocal, electron and multiphoton microscopy has shown that glioma cells and human glioma stem cells disperse through the brain in vivo by traveling preferentially along the perivascular compartment, a potential migration network surrounding the brain microvasculature. As glioma cells move throughout the perivascular network they dislodge glial endfeet from blood vessels and compromise adjacent brain tissue; this is later replaced by tumor cells. We have also generated preliminary data that a glycan binding protein, galectin-1, is essential for this growth mechanism. Down regulation of galectin-1 abolishes glioma growth in the brain in vivo, without affecting growth in vitro. These new data have several clinical consequences: (i) lymph drains from the brain through the perivascular compartment; its obstruction by gliomas would contribute to glioma-induced edema; (ii) human glioma tumors grow to large size before causing symptoms; glioma cell replacement of atrophied brain tissue could explain protracted and indolent tumor growth, and the delayed changes in total brain volume; (iii) inhibition of galectin-1 could represent a novel treatment of human gliomas. This proposal will (I) test the hypothesis that rodent and human glioma cells, and glioma stem cells grow preferentially along the perivascular space; (II) test the hypothesis that galectin-1 mediates glioma perivascular invasion and growth, and that inhibition of galectin-1 can be used as a novel therapeutic strategy; and (III) test the hypothesis that inhibition of galectin-1 will enhance specific anti-glioma immune responses. By progressing from glioma pathophysiology to molecular mechanisms of glioma migration to experimental therapeutics, we aim for our work to lead to novel early phase clinical translational trials for the treatment of human gliomas. Of note, our first clinical trial for gene therapy of human gliomas is approaching the start of patient recruitment (it was approved by FDA on 4/7/11 [IND 14574] and very recently by the University of Michigan IBC and IRB). Therefore, our laboratory is in a strong and realistic position to guide our research towards the translational implementation of novel clinical trials for this currently deadly human cancer.