Bone marrow derived neural stem cell therapy for glioma

描述（由申请人提供）：目前的胶质母细胞瘤治疗方法无法触及神经结构内的肿瘤细胞。然而，有效治疗的障碍与已知的丰富的自体骨髓神经干细胞（BM-NSCs）的生物学特性相匹配。了解肿瘤细胞和其他损伤区域的干细胞归巢机制不仅对了解基本的干细胞生物学很重要，而且对脑肿瘤和神经退行性疾病的干细胞治疗也很重要。我们的中心假设是，控制骨髓源性神经干细胞（BM-NSC）向胶质瘤血管生态位的趋向性的机制与介导NSC向稳态血管生态位迁移和从稳态血管生态位迁移的机制相同。我们将验证以下假设：SDF-1介导BM-NSCs向胶质瘤病理性血管生态位的迁移，以及癌症干细胞的迁移依赖于SDF-1，使这些细胞在大脑中“共同旅行者”。我们提出：目的1：在转基因自发性胶质瘤模型中验证BM-NSC向肿瘤血管生态位迁移依赖于CXCR4表达、CXCR4与SDF-1的相互作用、CXCR4受体信号传导以及PI3K/Akt通路的下游诱导的假设。目的2：在体外验证SDF1会增加BM-NSCs上a6整合素表达和EGFR表达的假设，以及这种作用会增加BM-NSCs对肿瘤内皮表面的粘附和对肿瘤条件培养基的趋向性。在自发性神经胶质瘤模型中，我们将验证阻断a6整合素将使细胞从肿瘤血管壁龛中分离的假设。我们还将验证阻断EGFR将限制BM-NSCs迁移潜力的假设。目的3：验证CSC对肿瘤血管生态位的侵袭依赖于CXCR4的假设。在一个自发的转基因小鼠胶质瘤模型中，验证脑胶质瘤- nscs和CSCs在胶质瘤血管壁龛内共定位的假设。

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.