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: 7886530
• 负责人: HUIYAN ZENG
• 金额: $ 35.28万
• 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/7886530
• 关键词: Adherence; Adherens Junction; Adult; Adverse effects; Angiogenic Factor; Antibodies; Area; Avastin; Binding Sites; Cell Proliferation; Cells; Colon; Colon Carcinoma; Complementary DNA; Complex; Data; Defect; Development; Dominant-Negative Mutation; Down-Regulation; ETS1 gene; Edema; Effectiveness; Endothelial Cells; Endothelium; Family member; Figs - dietary; Gases; Goals; Grant; Growth; 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; public health relevance; 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（3 mm3），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通透性中最重要的一种。 VEGF-A165 人源化抗体 Avastin 已被开发出来，并被证明可有效治疗多种类型的癌症。然而，阿瓦斯汀具有显着的毒副作用。因此，需要确定 VEGF 信号传导的下游靶点是否可以用作具有较小毒性作用的有希望的治疗靶点。我们最近的工作表明，在培养的内皮细胞和病理性血管生成中，孤儿核受体 TR3（小鼠类似物，Nur77）被 VEGF-A165 高度上调，并且它是 VEGF-A165 诱导的体外内皮细胞增殖和存活以及体内 Matrigel 血管生成所必需的。即使在不存在 VEGF-A165 的情况下，TR3 cDNA 的过表达也会在体外和体内基质胶血管生成中诱导内皮细胞增殖和存活。 TR3 的转录活性是其在血管生成中发挥作用所必需的。此外，B16 黑色素瘤的生长在 Nur77-/- 小鼠中被完全抑制，很可能是通过抑制肿瘤血管生成来实现的。 Nur77-/-小鼠没有明显的发育缺陷。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，我们将在目标 1 中研究小鼠内皮中 Nur77 活性受到抑制的转基因小鼠中的肿瘤生长。我们的第二个目标将研究 TR3/Nur77 通过破坏 VE-钙粘蛋白粘附连接的稳定性来调节肿瘤血管生成及其相关的微血管通透性。最后一个目标是，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癌症治疗方法。公共卫生相关性：肿瘤生长的机制在很大程度上尚不清楚。我们当前的提案将确定 Nur77 是癌症治疗的绝佳靶点。