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

基本信息

批准号：
8729867
负责人：
ALI SYED ARBAB
金额：
$ 30.43万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8729867
关键词：
AMD3100 Active Sites Adjuvant Adjuvant Therapy Angiogenesis Inhibitors Angiogenic Factor Animal Model Blood Vessels Bone Marrow Bone Marrow Cells CXCR4 Receptors CXCR4 gene Cell Transplants Cells Chemotactic Factors Clinical Complex Data Detection Diffusion Engraftment Future Glioblastoma Glioma Goals Growth Histocytochemistry Human Human Ubiquitin Hypervascular Hypoxia Imaging Techniques Immunohistochemistry Investigation Magnetic Resonance Imaging Measures Mediating Molecular Monitor Morphology Mus Nature Nude Mice Pathway interactions Pattern Peripheral Blood Mononuclear Cell Permeability Phase Population Protein Tyrosine Kinase Proteins Recruitment Activity Refractory Reporter Genes Research Research Personnel Resistance Role Site Stem cells Stromal Cell-Derived Factor 1 System Testing Time Tissues Transgenic Mice Transplantation Treatment Protocols Tumor Angiogenesis Tumor Volume Tyrosine Kinase Inhibitor Ubiquitin C Up-Regulation Vascular Endothelial Growth Factor Receptor Vascular Permeabilities Western Blotting angiogenesis bevacizumab cell motility density hypoxia inducible factor 1 imaging modality in vivo inhibitor/antagonist migration mouse model neovascularization novel optical imaging promoter receptor restoration small molecule treatment strategy tumor tumor growth tumor progression vasculogenesis

项目摘要

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）的血管丰富性和相关的活跃血管生成，研究人员添加了抗血管生成治疗作为辅助剂，以使血管正常化并控制异常血管生成。抗血管生成治疗会扰乱肿瘤脉管系统，导致明显缺氧。在 GBM 中，缺氧会导致缺氧诱导因子 1-α (HIF-1) 上调。 HIF-1 上调 SDF-1，SDF-1 反过来又可能招募各种促血管生成的骨髓来源细胞。任何吸引更多 EPC 的治疗都可能促进新血管形成和促生长，这是抗血管生成治疗的矛盾效应。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，导致内皮祖细胞 (EPC) 或骨髓祖细胞 (BMPC)（不同类型的干细胞）迁移和积累，并且增强难治性肿瘤的血管生成。本研究的目的是通过制作嵌合小鼠模型并应用新型非侵入性、最先进的 MRI 和光学成像方法来监测肿瘤进展以及相关的外源性和内源性 EPC 的迁移，从而阐明难治性胶质瘤的新生血管形成机制。我们将分三个阶段进行研究：（1）建立嵌合小鼠模型，用转基因小鼠（C57BL/6-Tg（UBC）骨髓中采集的骨髓细胞替代亚致死剂量照射的无胸腺小鼠的骨髓。 -GFP)30Scha/J)，在人泛素 C 启动子的控制下表达 GFP 蛋白。这些嵌合小鼠将用于产生原位人类神经胶质瘤。 (2)通过MRI测定肿瘤血管通透性、增强模式、分布体积和扩散参数的变化，以及vetanalib或AMD3100治疗后肿瘤及周围组织中不同血管生成因子及其相关受体的变化(或更新有效的 CXCR4 抑制剂），单独或组合； (3) 在使用 vetanalib 或 AMD3100（或更新的强效 CXCR4 抑制剂）单独或联合进行抗血管生成治疗期间，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 EPC 的参与情况，结果将是与血管生成因子和受体的表达相关。内源性 BMPC 和外源性 EPC 在肿瘤新生血管形成中的参与也将被比较和关联。预计干细胞在抗血管生成治疗中具有强大的作用。不同治疗方案后内源性或施用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过程中发挥作用。的相关性累积的干细胞与 MRI 结果和不同血管生成受体的表达将有助于临床医生在考虑抗血管生成治疗时修改治疗策略。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Myeloid Derived Suppressor Cells: Fuel the Fire.

DOI：
10.4172/2168-9652.1000e123
发表时间：
2014-08
期刊：
Biochemistry & physiology
影响因子：
0
作者：
Achyut BR;Arbab AS
通讯作者：
Arbab AS

Encapsulation of Anticancer Drugs (5-Fluorouracil and Paclitaxel) into Polycaprolactone (PCL) Nanofibers and In Vitro Testing for Sustained and Targeted Therapy.

DOI：
10.1166/jbn.2017.2353
发表时间：
2017-04
期刊：
Journal of biomedical nanotechnology
影响因子：
2.9
作者：
Iqbal S;Rashid MH;Arbab AS;Khan M
通讯作者：
Khan M

Vascular mimicry in glioblastoma following anti-angiogenic and anti-20-HETE therapies.

DOI：
10.14670/hh-11-856
发表时间：
2017-09
期刊：
Histology and histopathology
影响因子：
2
作者：
Angara K;Rashid MH;Shankar A;Ara R;Iskander A;Borin TF;Jain M;Achyut BR;Arbab AS
通讯作者：
Arbab AS

Cancer Therapeutics Following Newton's Third Law.

遵循牛顿第三定律的癌症治疗。