Characterizing tumor endothelial cell abnormalities to develop rational anti-angi

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在30多年前首次提出。目前大约有11种抗血管生成药物处于临床试验阶段。但到目前为止，大多数临床研究的结果都令人失望。抗血管生成（抗内皮）疗法背后的理念是，内衬肿瘤血管的内皮细胞是均匀的、正常的、不可变的，与肿瘤细胞相比，不会产生抗损伤性。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（如异位钙化）和显著的异质性。内皮细胞可能通过多种获得性机制逃避生长肿瘤的抗血管生成策略。例如，肿瘤特异性内皮细胞可能来源于多种细胞类型，包括发芽内皮细胞、骨髓源性血管祖细胞、跨分化骨髓细胞和多能中胚层干细胞。令人惊讶的是，如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。为了解决这一问题，我们的目标是：1)使用乳腺和前列腺癌转基因小鼠模型从乳腺和前列腺肿瘤中分离和表征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)测定成体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)利用激光捕获微解剖和微阵列技术，鉴定肿瘤特异性内皮细胞从早期肿瘤发展为腺癌的分子特征。目前尚不清楚为什么抗血管生成疗法在治疗癌症方面有很大的希望，却没有在临床上取得成功。我们的研究旨在通过对新分离细胞的严格表征和高通量基因分析来识别新的基因和基因网络，更好地了解肿瘤特异性内皮细胞的生物学。长期目标是利用这一新知识合理设计更有效的抗血管生成策略。

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.