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: 7708266
• 负责人: Andrew Carl Dudley
• 金额: $ 13.07万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 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/7708266
• 关键词: Accounting; Acidosis; Address; Adenocarcinoma; Adult; Angiogenesis Inhibitors; Antibodies; Blood; Blood Circulation; Blood Vessels; Bone Marrow; Breast; Carcinoma; Cartilage; Cataloging; Catalogs; Cell Line; Cells; Clinic; Clinical Research; Clinical Trials; Cytogenetics; Development; Diagnostic Neoplasm Staging; Dissection; Drug resistance; Drug usage; Employee Strikes; Endothelial Cells; Endothelium; Epigenetic Process; Gene Expression; Genes; Goals; Growth; Heterogeneity; Homing; Human; Hypoxia; Knowledge; Laboratories; Lasers; Location; Mammary Neoplasms; Measures; Mediating; Mesenchymal Stem Cells; Methodology; Modeling; Molecular; Molecular Profiling; Morphology; Mus; Myeloid Cells; Neoplasm Metastasis; Neoplasms; Neoplasms in Vascular Tissue; Nutrient; Oxygen; Principal Investigator; Process; Property; Prostate; Prostate carcinoma; Prostatic Neoplasms; Resistance; Resistance development; Solid Neoplasm; Source; Specimen; Staging; Stem cells; Techniques; Testing; Transgenic Mice; Tumor Biology; Tumor Cell Line; Tumor stage; Variant; Vascular calcification; angiogenesis; antiangiogenesis therapy; base; bone; calcification; cancer therapy; cell type; deprivation; design; feeding; genome-wide; mouse model; neoplastic cell; novel; progenitor; resistance mechanism; success; tumor; tumor growth; tumor progression; vasculogenesis

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）：30年前首次提出了可以通过破坏肿瘤相关血管来消除肿瘤的想法。如今，在临床试验中，大约有11种抗血管生成药物。但是迄今为止，大多数临床研究的结果令人失望。抗血管生成（抗内皮）疗法背后的想法是，肿瘤血管内皮细胞是均匀的，正常的，不可突变，并且与肿瘤细胞相比不会产生DMG耐药性。然而，最近的研究表明形态和分子变化（例如异位钙化）和肿瘤特异性内皮细胞中引人注目的异质性。由增长的肿瘤征集的内皮细胞可以通过多种获得的机制来逃避抗血管生成策略。例如，肿瘤特异性的内皮细胞可以源自多种细胞类型，包括发芽内皮，骨髓衍生的血管祖细胞，跨分化的髓样细胞和多功能中胚层干细胞。因此，令人惊讶的是，当今大多数抗血管生成疗法经常在实验室的正常内皮细胞系上进行测试。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并表征肿瘤特异性内皮细胞与乳腺癌和前列腺肿瘤。 2）确定肿瘤血管钙化与肿瘤进展与转移之间的关系。 3）确定成年间充质干细胞在肿瘤小鼠中的肿瘤特异性“归巢”和血管分化潜力。 4）并使用激光捕获微截断和微阵列来鉴定肿瘤特异性内皮细胞中的分子特征，因为肿瘤从最早的肿瘤发展到腺癌。尚不清楚为什么在诊所中没有成功的抗血管生成疗法（在癌症治疗方面都有很大的希望）。我们的研究试图通过严格的新鲜分离细胞和高通量基因分析来更好地了解肿瘤特异性内皮细胞的生物学，以鉴定新的基因和基因网络。长期的目标是利用这种新知识进行更有效的抗血管生成策略的理性设计。 相关性：抗血管生成基于以下原理：通过使用药物靶向血管以血液，氧气和养分为目标，可以缩小肿瘤的原理。但是，我们对肿瘤血管的基本知识受到严重限制。我们的研究将更好地表征肿瘤特异性血管的生物学，其长期目标是将新知识用于抗血管生成疗法的合理设计。