Orphan Nuclear Receptor TR3 in tumor angiogenesis and associated microvessel perm

总结 为了生长超过最小尺寸（3 mm 3），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的目的。在众多的血管生成因子中，VEGF-A 已被证明是肿瘤血管生成和相关微血管通透性中最重要的一个 到血浆蛋白质。已经开发了针对VEGF-A165的人源化抗体Avastin，并且显示其是 有效治疗多种癌症。然而，Avastin具有显著的毒副作用。因此 需要鉴定VEGF信号传导的下游靶点是否可以用作有希望的治疗剂 毒性较小的目标。我们最近的工作表明，孤儿核受体TR 3（小鼠） Nur 77）在培养的内皮细胞和病理性血管内皮细胞中被VEGF-A165高度上调。 血管生成和VEGF-A165诱导的体外内皮细胞增殖和存活所需 和Matrigel血管生成。TR 3 cDNA过表达诱导内皮细胞增殖， 体外存活和体内Matrigel血管生成，甚至在没有VEGF-A165的情况下。转录 TR 3的活性是其在血管生成中的功能所必需的。此外，B16黑色素瘤生长完全被抑制。 在Nur 77-/-小鼠中抑制，最可能通过抑制肿瘤血管生成。Nur 77-/-小鼠与正常小鼠相比， 发育缺陷我们的总体假设是TR 3/Nur 77通过调节肿瘤生长， 血管生成和相关的微血管通透性。为了证明我们的假设， 分子机制，我们将研究Nur 77活性在小鼠中被抑制的转基因小鼠的肿瘤生长 Aim 1中的内皮细胞。我们的第二个目标是研究TR 3/Nur 77调节肿瘤血管生成及其作用机制。 相关的微血管通透性通过VE-钙粘蛋白粘附连接的不稳定。在最后一个目标中， 我们将描述TR 3调节VE-钙粘蛋白表达的转录机制。的 这项研究的信息不仅将增强我们对肿瘤发生的病理生理学的理解， 而且还帮助我们开发用于治疗癌症的有效治疗方法。

Summary 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.