Targeting Pericytes in Cancer

针对癌症中的周细胞

基本信息

批准号：
8403632
负责人：
RAGHU KALLURI
金额：
$ 31.21万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403632
关键词：
Ablation Basement membrane CSPG4 gene Cell surface Cells Cessation of life Characteristics Chondroitin Sulfate Proteoglycan Coupled Diagnostic Neoplasm Staging Endothelial Cells Evaluation Exhibits Fibroblasts Fluorescence Genetic Genomics Grant Growth Hypoxia Imatinib Immune Infiltration Inflammatory Infiltrate Intervention Laboratories Lung MAPK14 gene Malignant Neoplasms Mammary Neoplasms Mediating Mesenchymal Mouse Protein Mus Mutation Neoplasm Metastasis PDGFRB gene Pathway interactions Pericytes Phase Platelet-Derived Growth Factor Receptor Platelet-Derived Growth Factor beta Receptor Play Primary Neoplasm Proliferating Proteins Reagent Role Snails Sorting - Cell Movement Staging Systemic disease Testing Thymidine Kinase Transgenic Mice Tumor Angiogenesis Tumor stage Viral angiogenesis cancer cell cell type design epithelial to mesenchymal transition inhibitor/antagonist malignant breast neoplasm mitogen-activated protein kinase p38 mouse model novel promoter public health relevance receptor recombinase research clinical testing slug therapeutic target tumor tumor growth tumor progression vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): Tumor growth, angiogenesis, and invasion depends on the recruitment and coordinated activity of different cell types populating the tumor stroma, such as endothelial cells, fibroblasts, pericytes, and infiltrating inflammatory cells. Although tumor associated vessels share similar components to normal vessels, including endothelial cells, basement membranes and pericytes, these vessels are abnormal, tortuous and leaky. While the functional role of endothelial cells in the context of tumor angiogenesis and vasculogenesis is extensively studied, the contribution of pericytes/perivascular cells in cancer progression and metastasis is poorly understood. Several studies suggest that targeting pericytes can control the rate of angiogenesis and growth of late stage tumors; however it is imperative to perform functional studies to evaluate the consequence of anti-pericyte therapy before moving these agents into clinical testing phase. In this regard, NG2, a novel cell surface chondroitin sulfate proteoglycan, is shown to be a reliable marker of pericytes/perivascular cells, along with the PDGF receptor 2 (PDGFR2). This grant proposes to perform functional studies utilizing these markers in transgenic mice setting to elucidate the role of pericytes in breast cancer progression and lung metastasis. This application will test the central hypothesis that "pericytes associated with primary breast tumors determine the rate of cancer progression and emergence lung metastasis". The proposal will functionally explore therapeutic targeting of pericytes using novel genetic mouse models in combination with novel pharmacological interventions using targeted therapy. The specific aims in this proposal are: 1) To determine the functional contribution of pericytes in primary breast cancer progression and lung metastasis, 2) To investigate the contribution of epithelial to mesenchymal transition in hypoxia induced lung metastasis, and 3) To determine the role of PDGFR2 in lung metastasis.

描述（由申请人提供）：肿瘤生长、血管生成和侵袭取决于肿瘤基质中不同细胞类型的募集和协调活性，例如内皮细胞、成纤维细胞、周细胞和浸润性炎症细胞。尽管肿瘤相关血管与正常血管具有相似的成分，包括内皮细胞、基底膜和周细胞，但这些血管是异常的、曲折的和渗漏的。虽然内皮细胞在肿瘤血管生成和血管发生中的功能作用得到了广泛研究，但周细胞/血管周围细胞在癌症进展和转移中的贡献却知之甚少。多项研究表明，靶向周细胞可以控制晚期肿瘤的血管生成和生长速度。然而，在将这些药物进入临床测试阶段之前，必须进行功能研究以评估抗周细胞治疗的效果。在这方面，NG2（一种新型细胞表面硫酸软骨素蛋白多糖）与 PDGF 受体 2 (PDGFR2) 一起被证明是周细胞/血管周围细胞的可靠标记。该资助计划在转基因小鼠中利用这些标记物进行功能研究，以阐明周细胞在乳腺癌进展和肺转移中的作用。该应用程序将测试“与原发性乳腺肿瘤相关的周细胞决定癌症进展和出现肺转移的速度”的中心假设。该提案将使用新型遗传小鼠模型结合使用靶向治疗的新型药理学干预措施，在功能上探索周细胞的治疗靶向。该提案的具体目标是：1) 确定周细胞在原发性乳腺癌进展和肺转移中的功能贡献，2) 研究上皮到间质转化在缺氧诱导的肺转移中的贡献，3) 确定其作用PDGFR2 在肺转移中的作用。