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多年前首次提出了通过破坏肿瘤相关血管来根除肿瘤的想法。目前，大约有11种抗血管生成药物正在进行临床试验。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，与肿瘤细胞相比，肿瘤血管内衬的内皮细胞是同质的、正常的、不可突变的，并且不会产生药物抗性。然而，最近的研究表明，肿瘤特异性内皮细胞存在形态和分子变化（例如异位钙化）以及显着的异质性，这一基本假设受到了挑战。被生长中的肿瘤征召的内皮细胞可能通过多种获得性机制逃避抗血管生成策略。例如，肿瘤特异性内皮细胞可以来源于多种细胞类型，包括发芽内皮细胞、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。令人惊讶的是，今天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）使用转基因小鼠模型的乳腺癌和前列腺癌的肿瘤特异性内皮细胞的分离和表征。2)探讨肿瘤血管钙化与肿瘤进展和转移的关系。3)目的：研究成年骨髓间充质干细胞在荷瘤小鼠体内的肿瘤特异性归巢和血管分化潜能。4)并使用激光捕获显微切割和微阵列来识别肿瘤特异性内皮细胞中的分子标记，因为肿瘤从最早的瘤形成进展到腺癌。目前尚不清楚为什么在癌症治疗中有很大希望的抗血管生成疗法在临床上没有成功。我们的研究旨在通过对新鲜分离细胞的严格表征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，以识别新基因和基因网络。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：抗血管生成是基于这样的原理，即肿瘤可以通过使用药物靶向为它们提供血液、氧气和营养的血管而缩小。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描述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合理设计抗血管生成疗法。