Targeting Pericytes in Cancer

描述（由申请人提供）：肿瘤生长、血管生成和侵袭依赖于填充肿瘤基质的不同类型细胞的募集和协调活动，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、扭曲的和渗漏的。虽然内皮细胞在肿瘤血管生成和血管生成中的功能作用被广泛研究，但周细胞/血管周围细胞在癌症进展和转移中的作用却知之甚少。一些研究表明，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试验阶段之前，进行功能研究以评估抗周细胞治疗的后果是必要的。在这方面，NG2，一种新的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志物。该基金建议在转基因小鼠环境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。该应用程序将验证“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。该提案将利用新的遗传小鼠模型，结合使用靶向治疗的新型药物干预，功能性地探索周细胞的治疗靶向性。本课题的具体目的是：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)研究上皮细胞在缺氧诱导的肺转移中对间质转化的贡献；3)确定PDGFR2在肺转移中的作用。

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. PUBLIC HEALTH RELEVANCE: About 80% of cancer deaths are associated with systemic disease, also known as 'metastasis'. Many studies suggest that the genetic alterations that accumulate in the cancer cells define, in part, the metastatic potential. Nevertheless, components of the tumor stroma, such as fibroblasts, endothelial cells, and pericytes, may play a role in metastasis. Several studies suggest pericytes as new potential therapeutic targets to inhibit tumor angiogenesis and subsequently tumor growth. Our proposal is designed to functionally determine the contribution of pericytes in primary tumor growth and metastasis, and identify new therapies to inhibit metastasis.