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

 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中心作用。抗VEGF中和抗体和VEGFR激酶/多激酶抑制剂已被成功开发并广泛应用于临床。然而，肿瘤的VEGF靶向治疗除了毒副作用外，还面临疗效不足、耐药性和内在难治性等问题。因此，需要鉴定另外的血管生成靶标。最近，我们发现唐氏综合征候选区1亚型1 L（DSCR 1 - 1 L）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DSCR 1 - 1 L表达抑制体外内皮细胞增殖和VEGF诱导的小鼠Matrigel血管生成。此外，DSCR 1 - 1 L仅在人癌组织（卵巢和肾）的肿瘤脉管系统中表达，而不在正常组织中表达，这表明靶向DSCR 1 - 1 L比靶向VEGF/VEGFR具有更少的副作用。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-羟色胺诱导血管生成。我们的初步研究表明，DSCR 1 - 1 L也被组胺，5-羟色胺和PAF诱导，这表明靶向DSCR 1 - 1 L将抑制导致肿瘤血管生成的几个信号通路。具体目的是研究DSCR 1 - 1 L是否调控血管生成、肿瘤生长和转移。本研究将证明DSCR 1 - 1 L是一个新的抗血管生成的治疗靶点。因此，该应用程序具有翻译潜力。

 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.