Bone marrow derived neural stem cell therapy for glioma

描述(由申请人提供)：目前治疗胶质母细胞瘤的方法不能触及在神经结构内暗示自己的肿瘤细胞。然而，有效治疗的障碍与丰富的自体来源的骨髓神经干细胞(BM-NSCs)的已知生物学特性相匹配。了解干细胞是肿瘤细胞和其他损伤区域的宿主的机制，不仅对于了解基本的干细胞生物学，而且对于转化干细胞治疗脑瘤和神经退行性疾病的方法都很重要。我们的中心假设是，控制骨髓源性神经干细胞(BM-NSC)向胶质瘤血管壁龛迁移的机制与介导NSC向内环境平衡的血管壁龛迁移的机制是相同的。我们将测试这样的假设，即SDF-1介导BM-NSCs向胶质瘤病理血管壁龛的迁移，以及癌症干细胞迁移是SDF-1依赖的，使这些细胞在大脑中“同行”。我们建议：目的1：在转基因自发性胶质瘤模型中，验证BM-NSC迁移到肿瘤血管壁龛的假设依赖于CXCR4的表达、CXCR4与SDF-1的相互作用、CXCR4受体信号转导以及PI3K/Akt通路的下游诱导。目的：验证SDF1在体外可增加BM-NSCs整合素α6和EGFR的表达，增加BM-NSCs对肿瘤内皮细胞表面的黏附和对肿瘤条件培养液的趋向性。在一个自发的胶质瘤模型中，我们将测试阻断a6整合素将细胞从肿瘤血管壁龛中分离出来的假设。我们还将验证阻断EGFR将限制BM-NSCs迁移潜力的假设。目的：验证CSC侵袭肿瘤血管壁龛依赖于CXCR4的假设。在自发转基因小鼠脑胶质瘤模型中，验证BM-NSCs和CSCs共定位于脑胶质瘤血管壁龛内的假设。

DESCRIPTION (provided by applicant): Current therapies for glioblastoma are unable reach tumor cells that insinuate themselves within neural structures. However, the obstacles to effective therapy match the known biological properties of the abundant and autologous source of bone marrow derived neural stem cells (BM-NSCs). Understanding the mechanisms by which stem cells home to tumor cells and other areas of injury is important not only to understand basic stem cell biology but also to translate stem cell therapies for brain tumors and neurodegenerative disorders. Our central hypothesis is that the mechanisms that govern bone marrow derived neural stem cell (BM-NSC) tropism toward the glioma vascular niche are identical to those that mediate NSC migration to and from the homeostatic vascular niche. We will test the hypothesis that SDF-1 mediates the migration of BM-NSCs toward the pathological vascular niche of gliomas and that cancer stem cell migration is SDF-1 dependent, rendering these cells "co-travelers" in the brain. We propose to: AIM 1: Test the hypothesis that BM-NSC migration to the tumor vascular niche is dependent on CXCR4 expression, CXCR4 interaction with SDF-1, CXCR4 receptor signaling, and downstream induction of the PI3K/Akt pathway in a transgenic spontaneous glioma model. AIM 2: Test the hypothesis that SDF1 will increase a6 integrin expression and EGFR expression on BM-NSCs and that this effect will increase the adhesion of BM-NSCs to the surface of tumor endothelium and increase tropism toward tumor conditioned media, respectively in vitro. In a spontaneous glioma model, we will test the hypothesis that blocking a6 integrin will separate the cells from their tumor vascular niche. We will also test the hypothesis that blocking EGFR will limit the migratory potential of BM-NSCs. AIM 3: Test the hypothesis that CSC invasion to the tumor vascular niche is CXCR4 dependent. Test the hypothesis that BM-NSCs and CSCs co-localize within the glioma vascular niche in a spontaneous transgenic murine model of glioma.