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：
8287632
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/8287632
关键词：
Affect Animal Model Avastin Biological Markers 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.

长期目标和具体目的：最近的证据表明肿瘤内皮和周细胞，缠绕血管的细胞，可能是由循环的骨髓衍生而来的祖细胞或肿瘤腔中更成熟的细胞。该提议的核心假设是胶质母细胞瘤分泌因子调节骨髓衍生的周围祖细胞的募集和针对这些因素的治疗策略，招募了骨髓衍生和局部衍生的内皮周细胞将极大地阻碍直接从人胶质母细胞瘤衍生的异种移植物的生长不受文化的传播，可以概括人类的侵入性和血管性的动物模型胶质母细胞瘤。我们的具体目的是：（1）表征骨髓来源和当地的周细胞人胶质母细胞瘤异种移植物，尤其是肿瘤分泌因子，导致每个周细胞募集类型; （2）表征影响肿瘤内和循环数量的肿瘤分泌因子骨髓来源的周围祖细胞，并鉴定靶向周细胞的疗法的生物标志物；（3）确定靶向血管生成，血管生成以及局部和局部和人体胶质母细胞瘤异种移植物中体内骨髓衍生的周细胞。外行语言的公共描述：胶质母细胞瘤患者的中位生存期仍然存在在过去的十年中，贫穷和不变，在12-13个月中。在这种不良预后的原因中是胶质母细胞瘤的丰富血管，这是一个定义特征。该建议描述了一系列实验旨在发现胶质母细胞瘤获得其独特丰富的血管性的机制。在特别是，我们将确定导致内皮细胞募集的肿瘤分泌因子，细胞那条血管和周细胞的细胞在血管外部的细胞中对内皮的营养。通过研究局部肿瘤内内皮和周细胞的募集来源和循环骨髓衍生的前体细胞，我们希望获得全面的了解胶质母细胞瘤如何获得其独特丰富的脉管系统，这对于设计至关重要相关性（请参阅说明）：胶质母细胞瘤是一种恶性脑瘤诊断时间。据信，胶质母细胞瘤的丰富血液供应会导致这种不良的预后。该提案旨在发现并以治疗为目标胶质母细胞瘤的独特机制获得丰富的血液供应。