Orphan Nuclear Receptor TR3 in tumor angiogenesis and associated microvessel perm

孤儿核受体 TR3 在肿瘤血管生成和相关微血管生成中的作用

• 批准号: 8074948
• 负责人: HUIYAN ZENG
• 金额: $ 34.22万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-07 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074948
• 关键词: Adherence; Adherens Junction; Adult; Adverse effects; Angiogenic Factor; Antibodies; Area; Avastin; Binding Sites; Cell Proliferation; Cell Survival; Cells; Colon; Colon Carcinoma; Complementary DNA; Complex; Data; Defect; Development; Dominant-Negative Mutation; Down-Regulation; ETS1 gene; Edema; Effectiveness; Endothelial Cells; Endothelium; Family member; Gases; Goals; Grant; Growth; Health; Human; In Vitro; Intercellular Junctions; Knockout Mice; Length; Lewis Lung Carcinoma; Matrix Metalloproteinases; Mediating; Messenger RNA; Molecular; Mus; NR4A1 gene; Nucleic Acid Regulatory Sequences; Pathologic Neovascularization; Permeability; Plasma Proteins; Play; Proliferating; Protein Family; Proteins; Refuse Disposal; Regulation; Reporting; Role; Signal Transduction; Solid Neoplasm; Staging; Testing; Tetracyclines; Therapeutic; Tissues; Toxic effect; Transactivation; Transcription Coactivator; Transgenes; Transgenic Mice; Tumor Angiogenesis; Vascular Endothelial Growth Factors; Vascular Endothelium; Vascular blood supply; Wild Type Mouse; Work; adherent junction; analog; angiogenesis; cadherin 5; cancer therapy; cancer type; density; humanized antibody; in vivo; insight; matrigel; melanoma; nutrition; orphan nuclear receptor TR3; overexpression; promoter; therapeutic target; transcription factor; transgene expression; tumor; tumor growth; tumorigenesis

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.

描述（由申请人提供）：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。在许多血管生成因子中，VEGF-A已被证明是肿瘤血管生成和相关微血管对血浆蛋白渗透的最重要因子。一种针对VEGF-A165的人源化抗体Avastin已经被开发出来，并被证明对治疗几种类型的癌症有效。然而，阿瓦斯汀有明显的毒副作用。因此，需要确定VEGF信号的下游靶点是否可以作为有希望的治疗靶点，并且毒性作用较小。我们最近的工作表明，孤儿核受体TR3（小鼠类似物，Nur77）在培养的内皮细胞和病理性血管生成中被VEGF-A165高度上调，这是VEGF-A165诱导的内皮细胞体外增殖和存活以及体内Matrigel血管生成所必需的。即使在缺乏VEGF-A165的情况下，TR3 cDNA的过表达也能诱导内皮细胞在体外和体内的增殖和存活。TR3的转录活性是其在血管生成中的功能所必需的。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生长。为了证明我们的假设并深入了解分子机制，我们将在Aim 1中研究Nur77活性在小鼠内皮中被抑制的转基因小鼠的肿瘤生长。我们的第二个目标是研究TR3/Nur77通过破坏ve -钙粘蛋白粘附连接来调节肿瘤血管生成及其相关的微血管通透性。最后，我们将描述TR3调控VE-cadherin表达的转录机制。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，而且有助于我们开发有效的治疗癌症的方法。公共卫生相关性：肿瘤生长的机制在很大程度上是未知的。我们目前的建议将确定Nur77是癌症治疗的一个极好的靶点。