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: 8877789
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8877789
• 关键词: Adenoviruses; Adverse effects; Angiogenic Factor; Blood Vessels; Cell Proliferation; Clinic; Colon; Data; Down Syndrome; Endothelial Cells; Endothelium; Face; Goals; Growth; Histamine; Human; In Vitro; 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 Factor Receptor; Vascular Endothelial Growth Factors; angiogenesis; antiangiogenesis therapy; base; bevacizumab; disability; gain of function; kinase inhibitor; loss of function; matrigel; nanoparticle; neutralizing antibody; new therapeutic target; novel; public health relevance; 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）：血管生成对于实体瘤生长超过最小尺寸至关重要。在众多血管生成因子中，血管内皮生长因子（VEGF-A）在肿瘤血管生成和相关微血管对血浆蛋白的通透性中发挥着核心作用。抗VEGF中和抗体和VEGFR激酶/多种激酶抑制剂已研发成功并广泛应用于临床。然而，VEGF靶向治疗癌症除了毒副作用外，还面临着疗效不足、耐药性和固有难治性等问题。因此，需要鉴定额外的血管生成靶点。最近，我们发现唐氏综合症候选区域 1 亚型 1L (DSCR1-1L) 在培养的内皮细胞和 VEGF 诱导的小鼠血管生成模型中高度上调。敲低 DSCR1-1L 的表达可抑制体外内皮细胞增殖和 VEGF 诱导的小鼠基质胶血管生成。此外，DSCR1-1L仅在人类癌症组织（卵巢和肾脏）的肿瘤脉管系统中表达，但在正常组织中不表达，这表明靶向DSCR1-1L比靶向VEGF/VEGFR具有更少的副作用。据报道，组胺和血清素在肿瘤生长中发挥作用。最近，我们发现组胺和血清素诱导血管生成。我们的初步研究表明，DSCR1-1L 也由组胺、血清素和 PAF 诱导，这表明靶向 DSCR1-1L 将抑制导致肿瘤血管生成的多种信号通路。在具体目标中，我们将研究DSCR1-1L是否调节血管生成、肿瘤生长和转移。这项研究将证明 DSCR1-1L 是抗血管生成的新型治疗靶点。因此，该应用程序具有翻译潜力。