Characterizing and Targeting Tumoral Factors Recruiting Perivascular Progenitors

长期抑制和特定目的：最近的证据表明，肿瘤内皮细胞和 周细胞，包裹在血管周围的细胞，可以从循环的骨髓来源的 祖细胞或来自肿瘤腔中更成熟的细胞。这一提议的核心假设是， 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募集， 针对这些因子的治疗策略招募骨髓来源和局部来源的内皮细胞， 并且周细胞将显著阻碍直接来源于人胶质母细胞瘤的异种移植物的生长 在没有在培养物中传代的情况下，一种动物模型再现了人类肿瘤的侵袭性和血管分布， 胶质母细胞瘤我们的具体目标将是：（1）表征骨髓来源的和局部来源的周细胞， 人胶质母细胞瘤异种移植物，特别是导致每个周细胞募集的肿瘤分泌因子 （2）研究肿瘤分泌因子对肿瘤内和循环中肿瘤细胞数量的影响。 骨髓来源的血管周围祖细胞，并鉴定靶向周细胞的治疗的生物标志物;和（3） 确定靶向血管发生、血管生成和局部和局部治疗的联合治疗的效果， 人胶质母细胞瘤异种移植物中的骨髓源性周细胞。 通俗语言的公众描述：胶质母细胞瘤患者的中位生存期仍然是 在过去十年中，12-13个月的情况很差，没有变化。这种预后不良的原因之一是 胶质母细胞瘤丰富的血管分布是一个明显的特征。这个提议描述了一系列的实验 旨在揭示胶质母细胞瘤获得其独特丰富的血管分布的机制。在 特别是，我们将确定肿瘤分泌的因子，导致招募内皮细胞，细胞 以及周细胞，即位于血管外侧的细胞， 滋养内皮细胞。通过研究局部肿瘤内内皮细胞和周细胞的募集， 来源和循环骨髓来源的前体细胞，我们希望获得全面的 了解胶质母细胞瘤如何获得其独特的丰富的脉管系统，这将是至关重要的设计 相关性（参见说明）： 胶质母细胞瘤是一种恶性脑肿瘤，其中平均患者从肿瘤中存活仅超过一年。 诊断时间。胶质母细胞瘤丰富的血液供应被认为是导致这种不良预后的原因。 该提案旨在揭示和治疗靶向胶质母细胞瘤的独特机制， 获得了丰富的血液供应。

LONG-TERM OBJECTIVES AND SPECIFIC AIMS: 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 DESCRIPTION IN LAY LANGUAGE: 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 RELEVANCE (See instructions): 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.