Characterizing tumor endothelial cell abnormalities to develop rational anti-angi

表征肿瘤内皮细胞异常以开发合理的抗血管治疗

• 批准号: 8231654
• 负责人: Andrew Carl Dudley
• 金额: $ 13.36万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231654
• 关键词: Characterizing; tumor; endothelial; cell; abnormalities

DESCRIPTION (provided by applicant): The idea that tumors could be eradicated by destroying tumor-associated blood vessels was first proposed over 30 years ago. Today there are about 11 anti-angiogenic drugs in clinical trials. But the results of most clinical studies to date have so far been disappointing. The idea behind anti-angiogenesis (anti-endothelial) therapy is that the endothelial cells lining tumor blood vessels are homogeneous, normal, are not mutable, and will not develop dmg resistance in contrast to tumor cells. However, that basic assumption has been challenged by recent studies showing morphological and molecular changes (e.g. ectopic calcification) and striking heterogeneity in tumor-specific endothelial cells. Endothelial cells conscripted by a growing tumor may evade anti-angiogenic strategies through diverse, acquired mechanisms. For example, tumor-specific endothelial cells may be derived from multiple cell types, including sprouting endothelium, bone marrow- derived vascular progenitors, trans-differentiated myeloid cells, and multi-potent mesodermal stem cells. It is surprising, then, that most anti-angiogenic therapies today are routinely tested on normal endothelial cell lines in the laboratory. To address this problem, our goals are: 1) To use transgenic mouse models of breast and prostate carcinoma to isolate and characterize tumor-specific endothelial cells from breast and prostate tumors. 2) To determine the relationship between tumor blood vessel calcification and tumor progression and metastasis. 3) To determine the tumor-specific "homing" and vascular differentiation potential of adult mesenchymal stem cells in tumor-bearing mice. 4) And to use laser capture micro-dissection and micro- arrays to identify a molecular signature in tumor-specific endothelial cells as tumors progress from the earliest neoplasia to adenocarcinoma. It is not known why anti-angiogenic therapies, which hold great promise in the treatment of cancer, have not succeeded in the clinic. Our study seeks to better understand the biology of tumor-specific endothelial cells through rigorous characterization of freshly isolated cells and high-throughput gene analysis to identify novel genes and gene networks. The long-term goal is to use this new knowledge for the rational design of more effective anti-angiogenic strategies. RELEVANCE: Anti-angiogenesis is based on the principle that tumors can be shrunk by using drugs to target the blood vessels feeding them with blood, oxygen, and nutrients. But our basic knowledge of tumor blood vessels is severely limited. Our study will better characterize the biology of tumor-specific blood vessels with the long- term goal of using this new knowledge towards the rational design of anti-angiogenic therapies.

描述（由申请人提供）：通过破坏肿瘤相关血管来根除肿瘤的想法最早是在30多年前提出的。目前大约有11种抗血管生成药物处于临床试验阶段。但迄今为止大多数临床研究的结果都令人失望。抗血管生成（抗内皮）疗法背后的想法是，肿瘤血管内壁的内皮细胞是同质的、正常的、不可变的，并且与肿瘤细胞相比不会产生药物抗性。然而，这一基本假设受到最近研究的挑战，这些研究显示肿瘤特异性内皮细胞的形态和分子变化（例如异位钙化）和惊人的异质性。生长中的肿瘤征募的内皮细胞可能通过多种后天机制逃避抗血管生成策略。例如，肿瘤特异性内皮细胞可以源自多种细胞类型，包括发芽内皮、骨髓来源的血管祖细胞、转分化的骨髓细胞和多能中胚层干细胞。那么，令人惊讶的是，当今大多数抗血管生成疗法都是在实验室中对正常内皮细胞系进行常规测试。为了解决这个问题，我们的目标是：1）使用乳腺癌和前列腺癌的转基因小鼠模型来分离和表征来自乳腺癌和前列腺肿瘤的肿瘤特异性内皮细胞。 2）确定肿瘤血管钙化与肿瘤进展、转移的关系。 3) 确定荷瘤小鼠中成体间充质干细胞的肿瘤特异性“归巢”和血管分化潜力。 4) 当肿瘤从最早的肿瘤进展到腺癌时，使用激光捕获显微解剖和微阵列来识别肿瘤特异性内皮细胞的分子特征。目前尚不清楚为什么在癌症治疗中前景广阔的抗血管生成疗法在临床上没有取得成功。我们的研究旨在通过对新鲜分离的细胞进行严格表征和高通量基因分析来识别新基因和基因网络，从而更好地了解肿瘤特异性内皮细胞的生物学。长期目标是利用这些新知识来合理设计更有效的抗血管生成策略。 相关性：抗血管生成的原理是，通过使用药物靶向为肿瘤提供血液、氧气和营养物质的血管，可以缩小肿瘤。但我们对肿瘤血管的基础知识非常有限。我们的研究将更好地表征肿瘤特异性血管的生物学特征，长期目标是利用这一新知识来合理设计抗血管生成疗法。