In vivo detection of involvement of endogenous BM progenitor cells in glioma

体内检测神经胶质瘤中内源性 BM 祖细胞的参与

• 批准号: 8811180
• 负责人: ALI SYED ARBAB
• 金额: $ 9.36万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811180
• 关键词: vivo; detection; involvement; endogenous; BM

DESCRIPTION (provided by applicant): Because of hypervascular nature of glioblastoma (GBM) and associated active angiogenesis, investigators have added anti-angiogenic treatment as an adjuvant to normalize blood vessels and control abnormal angiogenesis. Antiangiogenic therapy disturbs tumor vasculature, leading to marked hypoxia. In GBM, hypoxia leads to up-regulation of hypoxia inducible factor 1-alpha (HIF-1). HIF-1 up-regulates SDF-1, which in turn may recruit various pro-angiogenic bone marrow-derived cells. Any therapy that invites more EPCs might promote neovascularization and pro growth, a paradoxical effect of anti-angiogenic therapy. Therefore, we hypothesize that anti-angiogenic treatment using VEGFR inhibitors would initiate the release of pro-angiogenic factors, causing migration and accumulation of endothelial progenitor cells (EPCs) or bone marrow progenitor cells (BMPCs) (different types of stem cells), and enhanced angiogenesis in refractory tumors. The goal of this study is to elucidate neovascularization mechanisms in refractory glioma by making chimeric mouse model and applying novel non-invasive, state of the art MRI and optical imaging approach to monitor tumor progression and associated exogenous and endogenous EPCs' migration. We will conduct the research in three phases: (1) we will establish chimeric mouse model where bone marrow of sub-lethally irradiated athymic mouse will be replaced by bone marrow cells collected from bone marrow of transgenic mouse (C57BL/6-Tg(UBC-GFP)30Scha/J) that express GFP protein under the control of human ubiquitin C promoter. These chimeric mice will be used to generate orthotopic human glioma. (2) we'll determine the changes in tumor vascular permeability, enhancement patterns, distribution volume, and diffusion parameters by MRI, and changes in different angiogenic factors and their associated receptors in the tumor and surrounding tissues following the treatment with vetanalib or AMD3100 (or a newer potent CXCR4 inhibitor), separately or in combination; (3) we'll determine the involvement of endogenous BMPCs and exogenous EPCs by optical imaging and cellular MRI, respectively, during antiangiogenic treatments with vetanalib or AMD3100 (or a newer potent CXCR4 inhibitor), separately or in combination, and the findings will be correlated with the expression o angiogenic factors and receptors. Involvement of endogenous BMPCs and exogenous EPCs in tumor neovascularization will also be compared and correlated. It is anticipated that there is a strong role of stem cells during anti-angiogenic therapy. Differences in accumulation of the endogenous or administered stem cells following different treatment schedule will prove our hypothesis that there is a role for stem cells during anti-angiogenic treatment. Correlation of the accumulated administered stem cells with MRI findings and the expression of different angiogenic receptors will help clinicians to modify treatment strategy when anti-angiogenic therapy is considered.

描述（由申请人提供）：由于胶质母细胞瘤（GBM）的多血管性质和相关的活跃血管生成，研究者增加了抗血管生成治疗作为辅助治疗，以使血管正常化并控制异常血管生成。抗血管生成治疗扰乱肿瘤血管系统，导致显著缺氧。在GBM中，缺氧导致缺氧诱导因子1-α（HIF-1）的上调。HIF-1上调SDF-1，SDF-1反过来可以募集各种促血管生成的骨髓源性细胞。任何能诱导更多EPCs的疗法都可能促进新生血管形成和促生长，这是抗血管生成疗法的一种矛盾效应。因此，我们假设使用VEGFR抑制剂的抗血管生成治疗将启动促血管生成因子的释放，引起内皮祖细胞（EPC）或骨髓祖细胞（BMPC）（不同类型的干细胞）的迁移和积聚，并增强难治性肿瘤中的血管生成。本研究的目的是通过建立嵌合体小鼠模型，并应用新的非侵入性的、最先进的MRI和光学成像方法来监测肿瘤的进展和相关的外源性和内源性EPCs的迁移，来阐明难治性胶质瘤中的新生血管形成机制。本研究分三个阶段进行：（1）建立嵌合小鼠模型，其中将亚致死剂量照射的无胸腺小鼠的骨髓用从人泛素C启动子控制下表达GFP蛋白的转基因小鼠（C57 BL/6-Tg（UBC-GFP）30 Scha/J）的骨髓中收集的骨髓细胞替代。这些嵌合小鼠将用于产生原位人神经胶质瘤。(2)我们将通过MRI确定肿瘤血管通透性、增强模式、分布体积和扩散参数的变化，以及在用vetanalib或AMD 3100治疗后肿瘤和周围组织中不同血管生成因子及其相关受体的变化（或较新的强效CXCR 4抑制剂）;（3）我们将分别通过光学成像和细胞MRI确定内源性BMPC和外源性EPCs的参与，在单独或联合使用vetanalib或AMD 3100（或新的强效CXCR 4抑制剂）进行抗血管生成治疗期间，这些发现将与血管生成因子和受体的表达相关。内源性BMPC和外源性EPCs在肿瘤新生血管形成中的参与也将被比较和关联。预期干细胞在抗血管生成治疗期间具有强大的作用。不同治疗方案后内源性或施用的干细胞积累的差异将证明我们的假设，即干细胞在抗血管生成治疗期间起作用。相关性 当考虑抗血管生成治疗时，累积施用的干细胞与MRI结果和不同血管生成受体的表达将帮助临床医生修改治疗策略。