Characterizing and Targeting Tumoral Factors Recruiting Perivascular Progenitors

描述(由申请人提供)：项目摘要：最近的证据表明，肿瘤内皮细胞和周细胞，即包裹血管的细胞，可以来自循环中的骨髓来源的前体细胞，也可以来自肿瘤腔中更成熟的细胞。这一建议的中心假设是，胶质母细胞瘤分泌的因子调节骨髓来源的血管周围祖细胞的招募，并且针对这些因子招募骨髓来源和局部来源的内皮细胞和周细胞的治疗策略将显著阻碍直接源于人胶质母细胞瘤的异种移植的生长，而不通过培养传代，这是一种概括人类胶质母细胞瘤侵袭性和血运的动物模型。我们的具体目标将是：1)鉴定人胶质母细胞瘤移植瘤中骨髓来源和局部来源的周细胞，特别是导致每种周细胞类型募集的肿瘤分泌因子；2)表征影响肿瘤内和循环中骨髓来源的血管周细胞前体细胞数量的肿瘤分泌因素，并确定针对周细胞的治疗的生物标志物；以及3)确定针对血管生成、血管生成以及体内局部和骨髓来源的周细胞的联合治疗的效果。公共卫生相关性：胶质母细胞瘤患者的中位生存期一直很低，在过去十年中保持不变，为12-13个月。预后不良的原因之一是胶质母细胞瘤丰富的血管，这是一个明显的特征。这项建议描述了一系列旨在揭示胶质母细胞瘤获得其独特丰富血管的机制的实验。特别是，我们将确定导致内皮细胞和周细胞招募的肿瘤分泌因子，周细胞是血管外部的细胞，为内皮提供营养。通过研究从局部肿瘤内来源和从循环中的骨髓来源的前体细胞中招募内皮细胞和周细胞，我们希望对胶质母细胞瘤如何获得其独特的丰富的血管系统有一个全面的了解，这将是设计... 公共卫生相关性：胶质母细胞瘤是一种恶性脑瘤，患者从确诊之日起平均存活仅一年多。胶质母细胞瘤丰富的血液供应被认为是造成这种不良预后的原因之一。这项建议旨在揭示胶质母细胞瘤获得丰富血液供应的独特机制，并在治疗上针对这一机制。

DESCRIPTION (provided by applicant): Project Summary: Recent evidence suggests that tumor endothelium and pericytes, cells which wrap around blood vessels, can arise from either circulating marrow-derived progenitors or from more mature cells in the tumor cavity. The central hypothesis of this proposal is that glioblastoma-secreted factors regulate the recruitment of marrow-derived perivascular progenitor cells, and that a therapeutic strategy targeting these factors recruiting marrow-derived and locally-derived endothelium and pericytes will significantly impede the growth of xenografts derived directly from human glioblastomas without passaging in culture, an animal model that recapitulates the invasiveness and vascularity of human glioblastoma. Our specific aims will be: 1) To characterize marrow-derived and locally-derived pericytes in human glioblastoma xenografts, particularly tumor-secreted factors leading to recruitment of each pericyte type; 2) To characterize tumor-secreted factors influencing the number of intratumoral and circulating marrow-derived perivascular progenitor cells and identify biomarkers of therapies targeting pericytes; and 3) To determine the effects of combined treatment targeting vasculogenesis, angiogenesis, and locally and marrow-derived pericytes in vivo in human glioblastoma xenografts. Public Health Relevance: The median survival for glioblastoma patients has remained poor and unchanged over the past decade, at 12-13 months. Among the causes of this poor prognosis is the rich vascularity of glioblastoma, a defining feature. This proposal describes a series of experiments designed to uncover the mechanisms by which glioblastoma acquires its uniquely rich vascularity. In particular, we will identify tumor-secreted factors that lead to the recruitment of endothelial cells, the cells that line the blood vessels, and pericytes, the cells on the outside of the blood vessels that provide nourishment to endothelium. By studying recruitment of endothelium and pericytes from local intratumoral sources and from circulating bone marrow-derived precursor cells, we hope to obtain a comprehensive understanding of how glioblastoma acquires its uniquely rich vasculature, which will be essential to designing... Public Health Relevance: Glioblastoma is a malignant brain tumor in which the average patient survivals barely over one year from the time of diagnosis. The rich blood supply of glioblastoma is believed to contribute to this poor prognosis. This proposal seeks to uncover and therapeutically target the unique mechanisms by which glioblastoma acquires its rich blood supply.