Down Syndrome Candidate Region 1 isoform 1L in tumor growth and metastasis

唐氏综合症候选区域 1 亚型 1L 在肿瘤生长和转移中的作用

• 批准号: 9043841
• 负责人: HUIYAN ZENG
• 金额: $ 8.7万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043841
• 关键词: Adenoviruses; Adverse effects; Angiogenic Factor; Blood Vessels; Cell Proliferation; Clinic; Colon; Data; Down Syndrome; Endothelial Cells; Endothelium; Face; Goals; Growth; Health; Histamine; Human; In Vitro; KDR gene; Kidney; Knowledge; Lead; Malignant Neoplasms; Mission; Modeling; Mus; Neoplasm Metastasis; Normal tissue morphology; Outcome; Ovarian Tissue; Permeability; Phosphotransferases; Plasma Proteins; Play; Protein Isoforms; Public Health; Reporting; Research; Resistance; Role; Serotonin; Signal Pathway; Small Interfering RNA; Solid Neoplasm; Stomach; System; Testing; Tetracyclines; Transgenes; Transgenic Mice; Translations; Tumor Angiogenesis; Vascular Endothelial Growth Factors; angiogenesis; antiangiogenesis therapy; base; bevacizumab; disability; gain of function; kinase inhibitor; knock-down; loss of function; matrigel; nanoparticle; neutralizing antibody; new therapeutic target; novel; overexpression; selective expression; targeted treatment; therapeutic angiogenesis; tumor; tumor growth

 DESCRIPTION (provided by applicant): Angiogenesis is critical for solid tumor growth beyond minimal size. Among many angiogenic factors, Vascular Endothelial Growth Factor (VEGF-A) plays a central role in tumor angiogenesis and associated microvessel permeability to plasma proteins. Anti-VEGF neutralizing antibodies and VEGFR kinase/multiple kinase inhibitors have been successfully developed and widely used in the clinic. However, in addition to their toxic side effect, the VEGF-targeted therapy in cancer faces the problems of insufficient efficacy, resistance and intrinsic refractoriness. Therefore, it is desirable to identify additional angiogenesis targets. Recently, we found that Down Syndrome Candidate Region 1 isoform 1L (DSCR1-1L) is highly up-regulated in cultured endothelial cells and in mouse angiogenesis model induced by VEGF. Knockdown the expression of DSCR1-1L inhibits endothelial cell proliferation in vitro and Matrigel angiogenesis in mice induced by VEGF. Further, DSCR1-1L is exclusively expressed in tumor vasculature of human cancer tissues (ovarian and kidney), but not in normal tissues, suggesting that targeting DSCR1-1L has less side effect than targeting VEGF/VEGFR. It was reported that histamine and serotonin play a role in tumor growth. Recently, we found that histamine and serotonin induce angiogenesis. Our preliminary studies demonstrate that DSCR1-1L is also induced by histamine, serotonin and PAF, suggesting that targeting DSCR1-1L will inhibit several signaling pathways that lead to tumor angiogenesis. In specific Aim, we will study whether DSCR1-1L regulates angiogenesis, tumor growth and metastasis. This research will demonstrate that DSCR1-1L is a novel therapeutic target for anti-angiogenesis. Hence, this application has translation potential.

 描述(由申请人提供)：血管生成对于实体肿瘤的生长至关重要，超过最小尺寸。在众多的血管生成因子中，血管内皮生长因子(VEGF-A)在肿瘤血管生成和相关的微血管对血浆蛋白的通透性中起着核心作用。目前已成功研制出抗血管内皮生长因子中和抗体和VEGFR激酶/多激酶抑制剂，并广泛应用于临床。然而，除了毒副作用外，肿瘤的血管内皮生长因子靶向治疗还面临着疗效不足、耐药性和内在顽固性等问题。因此，需要确定更多的血管生成靶点。最近，我们发现唐氏综合征候选区域1亚型1L(DSCR1-1L)在培养的血管内皮细胞和由血管内皮生长因子诱导的小鼠血管生成模型中高度上调。抑制DSCR1-1L的表达可抑制血管内皮细胞增殖和血管生成。此外，DSCR1-1L仅在人肿瘤组织(卵巢和肾脏)的肿瘤血管中表达，而在正常组织中不表达，这表明靶向DSCR1-1L的副作用比靶向VEGF/VEGFR的要小。据报道，组胺和5-羟色胺在肿瘤生长中起作用。最近，我们发现组胺和5-羟色胺可以诱导血管生成。我们的初步研究表明，DSCR1-1L也可以被组胺、5-羟色胺和PAF诱导，这表明靶向DSCR1-1L将抑制几个导致肿瘤血管生成的信号通路。有针对性地，我们将研究DSCR1-1L是否对血管生成、肿瘤生长和转移有调节作用。本研究将证明DSCR1-1L是一种新的抗血管生成的治疗靶点。因此，这个应用程序具有翻译潜力。