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Characterizing and Targeting Tumoral Factors Recruiting Perivascular Progenitors

表征和靶向招募血管周围祖细胞的肿瘤因素

基本信息

批准号：
8500475
负责人：
Manish Aghi
金额：
$ 19.07万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8500475
关键词：
Affect Animal Model Avastin Biological Markers Blood Circulation Blood Vessels Bone Marrow Cell Line Cells Clinical Combined Modality Therapy Derivation procedure Diagnosis Disease Dose Endothelial Cells Endothelium Gelatinase B Glioblastoma Glioma Growth Growth Factor Histologic Human Instruction Investigation Language Lead Left Malignant neoplasm of brain Marrow Mediating Neurosurgeon Operative Surgical Procedures Patient Care Patients Pericytes Phase Phase II Clinical Trials Postoperative Period Process Protein Kinase C Radiation Recruitment Activity Recurrence Regimen Resistance Role S-Phase Fraction Series Source Staging Stem Cell Factor Stem cells Therapeutic Time Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Vascular blood supply Work World Health Organization Xenograft procedure angiogenesis bevacizumab career cell type chemotherapy conventional therapy cytokine design effectiveness measure improved in vivo inhibitor/antagonist mortality neurosurgery neutralizing antibody outcome forecast precursor cell prevent progenitor receptor research study translational medicine tumor tumor growth vasculogenesis

项目摘要

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.

长期目标和具体目标：最近的证据表明肿瘤内皮和周细胞，即包裹血管的细胞，可以由循环骨髓来源的细胞产生祖细胞或更成熟的细胞在肿瘤腔中。该提案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募集，以及针对这些因子的治疗策略招募骨髓源性和局部源性内皮细胞和周细胞将显着阻碍直接源自人类胶质母细胞瘤的异种移植物的生长无需培养传代，重现人类侵袭性和血管分布的动物模型胶质母细胞瘤。我们的具体目标是：（1）表征骨髓来源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类型; (2) 表征影响瘤内和循环细胞数量的肿瘤分泌因素骨髓来源的血管周围祖细胞并识别针对周细胞的治疗的生物标志物；和（3）确定针对血管生成、血管生成以及局部和血管生成的联合治疗的效果人胶质母细胞瘤异种移植体内骨髓来源的周细胞。用通俗语言进行的公开描述：胶质母细胞瘤患者的中位生存期仍保持不变过去十年中 12-13 个月的情况很差且没有变化。造成这种不良预后的原因之一是胶质母细胞瘤的丰富血管，这是一个决定性特征。该提案描述了一系列实验旨在揭示胶质母细胞瘤获得其独特的丰富血管的机制。在特别是，我们将识别肿瘤分泌的因子，这些因子会导致内皮细胞的募集，这些细胞排列在血管上的细胞和周细胞，即血管外侧的细胞，提供给内皮细胞提供营养。通过研究局部瘤内内皮细胞和周细胞的募集来源和循环骨髓源性前体细胞，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脉管系统，这对于设计至关重要相关性（参见说明）：胶质母细胞瘤是一种恶性脑肿瘤，患者平均存活期仅一年多诊断时间。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。该提案旨在揭示并治疗靶向胶质母细胞瘤的独特机制获得其丰富的血液供应。