Targeting Pericytes in Cancer

描述（由申请方提供）：肿瘤生长、血管生成和侵袭取决于肿瘤间质中不同细胞类型（如内皮细胞、成纤维细胞、周细胞和浸润性炎性细胞）的募集和协调活性。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知之甚少。一些研究表明，靶向周细胞可以控制血管生成的速率和晚期肿瘤的生长;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结果。在这方面，NG 2，一种新的细胞表面硫酸软骨素蛋白聚糖，被证明是周细胞/血管周细胞的可靠标志物，沿着PDGF受体2（PDGFR 2）。这项资助计划利用这些标记物在转基因小鼠中进行功能研究，以阐明周细胞在乳腺癌进展和肺转移中的作用。本申请将检验中心假设，即“与原发性乳腺肿瘤相关的周细胞决定癌症进展和肺转移的发生率”。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，在功能上探索周细胞的治疗靶向。本提案的具体目的是：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）研究上皮细胞向间质细胞转化在缺氧诱导的肺转移中的贡献，以及3）确定PDGFR 2在肺转移中的作用。 公共卫生相关性：大约80%的癌症死亡与全身性疾病有关，也称为“转移”。许多研究表明，在癌细胞中积累的遗传改变部分地定义了转移潜力。然而，肿瘤间质的成分，如成纤维细胞、内皮细胞和周细胞，可能在转移中起作用。一些研究表明周细胞作为新的潜在的治疗靶点，以抑制肿瘤血管生成和随后的肿瘤生长。我们的建议旨在从功能上确定周细胞在原发性肿瘤生长和转移中的作用，并确定抑制转移的新疗法。

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.