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无法到达潜伏在神经结构内的肿瘤细胞。然而，有效治疗的障碍与骨髓来源的神经干细胞（BM-NSC）的丰富和自体来源的已知生物学特性相匹配。了解干细胞返回肿瘤细胞和其他损伤区域的机制不仅对了解基本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疗法也很重要。我们的中心假设是，管理骨髓源性神经干细胞（BM-NSC）向胶质瘤血管龛的向性的机制是相同的，那些介导的NSC迁移到和从稳态血管龛。我们将检验SDF-1介导BM-NSC向神经胶质瘤的病理血管龛迁移以及癌症干细胞迁移是SDF-1依赖性的这一假设，从而使这些细胞在脑中成为“共同旅行者”。我们建议：目标1：在转基因自发性胶质瘤模型中，检验BM-NSC迁移至肿瘤血管生态位依赖于CXCR 4表达、CXCR 4与SDF-1的相互作用、CXCR 4受体信号传导和PI 3 K/Akt通路的下游诱导的假设。 目标2：分别在体外测试SDF 1将增加BM-NSC上α 6整联蛋白表达和EGFR表达以及该作用将增加BM-NSC对肿瘤内皮表面的粘附和增加对肿瘤条件培养基的向性的假设。在自发性胶质瘤模型中，我们将检验阻断α 6整联蛋白将使细胞与其肿瘤血管龛分离的假设。我们还将检验阻断EGFR将限制BM-NSC迁移潜力的假设。 目的3：验证CSC侵袭肿瘤血管龛是CXCR 4依赖性的假说。在神经胶质瘤的自发转基因鼠模型中检验BM-NSC和CSC共定位于神经胶质瘤血管生态位内的假设。

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.