Orphan Nuclear Receptor TR3 in tumor angiogenesis and associated microvessel perm

描述(申请人提供)：为了生长超过最小尺寸(3mm3)，肿瘤必须产生新的血管供应(血管生成)，用于气体交换、细胞营养和废物处理。在众多的血管生成因子中，血管内皮生长因子-A被证明是在肿瘤血管生成和相关的微血管对血浆蛋白的通透性中最重要的一个。一种人源化的抗血管内皮生长因子-A165抗体阿瓦斯丁已经被开发出来，并被证明对几种类型的癌症有效。然而，阿瓦斯丁有显著的毒副作用。因此，确定血管内皮生长因子信号的下游靶点是否可以作为毒性较小的有希望的治疗靶点是可取的。我们最近的工作表明，孤儿核受体TR3(小鼠类似物，Nur77)在培养的血管内皮细胞中高度上调，在病理性血管生成中也是必需的，它是血管内皮细胞体外增殖和存活以及体内Matrigel血管生成所必需的。过表达TR3在体外诱导内皮细胞增殖和存活，在体内诱导Matrigel血管生成，即使在缺乏VEGF-A165的情况下也是如此。TR3的转录活性是其血管生成功能所必需的。此外，在Nur77-/-小鼠中，B16黑色素瘤的生长被完全抑制，很可能是通过抑制肿瘤血管生成。Nur77-/-小鼠无明显发育缺陷。我们的总体假设是，TR3/Nur77通过调节血管生成和相关的微血管通透性来调节肿瘤的生长。为了验证我们的假设并深入了解分子机制，我们将在目标1中研究NUR77活性在小鼠内皮细胞中受到抑制的转基因小鼠的肿瘤生长。我们的第二个目标将研究TR3/NUR77通过VE-钙粘附素黏附连接的失稳来调节肿瘤血管生成及其相关的微血管通透性。在最后一个目标中，我们将描述TR3调节VE-钙粘蛋白表达的转录机制。这项研究的信息不仅将加深我们对肿瘤发生的病理生理学的理解，而且有助于我们开发有效的治疗方法来治疗癌症。与公共卫生相关：肿瘤生长的机制在很大程度上是未知的。我们目前的提案将确定Nur77是癌症治疗的极佳靶点。

DESCRIPTION (provided by applicant): In order to grow beyond minimal size (3 mm3), tumors must generate a new vascular supply (angiogenesis) for the purpose of gas exchange, cell nutrition, and waste disposal. Among many angiogenic factors, VEGF-A has been shown to be the most important one in tumor angiogenesis and associated microvessel permeability to plasma proteins. A humanized antibody to VEGF-A165, Avastin, has been developed and shown to be effective in treating several types of cancers. However, Avastin has significant toxic side effects. Therefore, it is desirable to identify whether downstream targets of VEGF signaling can be used as promising therapeutic targets with less toxic effects. Our recent work showed that the orphan nuclear receptor TR3 (mouse analogue, Nur77) was highly upregulated by VEGF-A165 in cultured endothelial cells and in pathological angiogenesis and that it was required for VEGF-A165-induced endothelial cell proliferation and survival in vitro and Matrigel angiogenesis in vivo. Overexpression of TR3 cDNA induced endothelial cell proliferation and survival in vitro and in Matrigel angiogenesis in vivo, even in the absence of VEGF-A165. The transcriptional activity of TR3 is required for its function in angiogenesis. Further, B16 melanoma growth was completely inhibited in Nur77-/- mice, most likely through inhibition of tumor angiogenesis. Nur77-/- mice have no obvious developmental defect. Our overall hypothesis is that TR3/Nur77 regulates tumor growth through regulation of angiogenesis and associated microvessel permeability. To prove our hypothesis and gain insight into the molecular mechanisms, we will study tumor growth in transgenic mice that Nur77 activity is inhibited in mouse endothelium in Aim 1. Our second aim will investigate that TR3/Nur77 regulates tumor angiogenesis and its associated microvessel permeability by destabilization of VE-cadherin adherences junctions. In the last aim, we will delineate the transcriptional mechanisms by which TR3 regulates VE-cadherin expression. The information from this study will not only enhance our understanding of the pathophyiosiology of tumorigenesis but also help us to develop effective therapeutic approaches for treatment of cancers. PUBLIC HEALTH RELEVANCE: The mechanism of tumor growth is largely unknown. Our current proposal will identify that Nur77 is an excellent target for cancer therapy.