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.

首先提出了通过破坏肿瘤相关血管来根除肿瘤的想法 30多年前目前，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 迄今为止的临床研究结果令人失望。抗血管生成（anti-endothelial） 治疗的方法是肿瘤血管的内皮细胞是同质的、正常的、不可变异的， 并且与肿瘤细胞相比不会产生耐药性。然而，这一基本假设 最近的研究显示形态和分子变化（例如异位钙化）， 肿瘤特异性内皮细胞中的显著异质性。内皮细胞被生长的肿瘤征召 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。包括新生内皮细胞，骨髓源性 血管祖细胞、转分化的骨髓细胞和多能中胚层干细胞。是 令人惊讶的是，目前大多数抗血管生成疗法都是在正常内皮细胞上进行常规试验， 实验室里的线针对这一问题，我们的目标是：1）利用转基因小鼠乳腺癌模型， 和前列腺癌中分离和鉴定肿瘤特异性内皮细胞 肿瘤的2)确定肿瘤血管钙化与肿瘤进展的关系 和转移。3)为了确定肿瘤特异性“归巢”和血管分化潜能， 间充质干细胞在荷瘤小鼠。4)使用激光捕获显微切割和微阵列 当肿瘤从血管内皮细胞进展时， 最早的肿瘤到腺癌。目前尚不清楚为什么抗血管生成疗法，其中持有伟大的 在治疗癌症方面很有希望，但在临床上还没有成功。我们的研究旨在更好地了解 通过对新鲜分离的细胞进行严格表征， 高通量基因分析以鉴定新基因和基因网络。长期目标是利用这个 为合理设计更有效的抗血管生成策略提供了新的知识。