Tumor endothelial cell abnormalities

肿瘤内皮细胞异常

• 批准号: 8325609
• 负责人: Andrew Carl Dudley
• 金额: $ 24.9万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325609
• 关键词: Address; Adenocarcinoma; Adult; Angiogenesis Inhibitors; Blood; Blood Circulation; Blood Vessels; Bone Marrow; Bone Marrow Ablation; Breast Carcinoma; Cell Line; Cells; Clinic; Clinical Research; Clinical Trials; Clone Cells; Dissection; Drug resistance; Drug usage; Employee Strikes; Endothelial Cells; Endothelium; Engraftment; Genes; Goals; Heterogeneity; Homing; Human; Knowledge; Laboratories; Lasers; Mammary Neoplasms; Mesenchymal Stem Cells; Molecular; Molecular Profiling; Mouse Mammary Tumor Virus; Mus; Myeloid Cells; Neoplasm Metastasis; Neoplasms; Neoplasms in Vascular Tissue; Nutrient; Oxygen; PECAM1 gene; Prostate carcinoma; Prostatic Neoplasms; Stem cells; Testing; Transgenic Mice; Tumor Biology; antiangiogenesis therapy; base; bone; calcification; cancer therapy; cell type; design; feeding; mineralization; mouse model; neoplastic cell; novel; progenitor; programs; tumor; tumor progression

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 wlll not develop drug 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 marrowderived 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 microarrays 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.

肿瘤可以通过破坏肿瘤相关血管来根除的想法首次被提出。 30多年前。今天，大约有11种抗血管生成药物正在进行临床试验。但大多数人的结果 到目前为止，临床研究一直令人失望。抗血管生成(抗内皮细胞)背后的理念 治疗方法是使肿瘤血管内皮细胞均匀、正常、不变， 与肿瘤细胞相比，不会产生抗药性。然而，这一基本假设是 最近的研究显示形态和分子变化(例如异位钙化)和 肿瘤特异性内皮细胞的显著异质性。生长中的肿瘤征募内皮细胞 可能通过不同的获得性机制逃避抗血管生成策略。例如，肿瘤特异性 内皮细胞可能来源于多种细胞类型。包括发芽内皮、骨髓源性 血管祖细胞、跨分化髓系细胞和多潜能中胚层干细胞。它是 令人惊讶的是，如今大多数抗血管生成疗法都是在正常内皮细胞上进行常规测试 在实验室里排好队。为了解决这个问题，我们的目标是：1)使用转基因小鼠的乳房模型 和前列腺癌从乳腺和前列腺癌中分离和鉴定肿瘤特异性内皮细胞 肿瘤。2)确定肿瘤血管钙化与肿瘤进展的关系 和转移。3)确定成人肿瘤特异性“归巢”和血管分化潜能 荷瘤小鼠体内的间充质干细胞。4)使用激光捕获显微解剖和微阵列 为了确定肿瘤特异性内皮细胞在肿瘤从 最早的肿瘤转变为腺癌。目前尚不清楚为什么有效的抗血管生成疗法 在治疗癌症方面有希望，但在临床上都没有成功。我们的研究试图更好地理解 肿瘤特异性内皮细胞的生物学通过对新鲜分离的细胞和 高通量基因分析，以确定新的基因和基因网络。长期目标是利用这一点 为合理设计更有效的抗血管生成策略提供新的知识。