权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Analysis of newly identified anglogenic genes and the signal inhibition for tumor dormancy therapy

新发现的血管生成基因分析及肿瘤休眠治疗的信号抑制

基本信息

批准号：
14571141
负责人：
TANAKA Shinji
金额：
$ 2.56万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

In vivo progression to malignancy is characterized by the switch to an angiogenic phenotype. The angiogenic switch is a critical control point for tumor expansion. The ability of a tumor to become neovascularized permits rapid expansion of tumor growth and increases the likelihood of metastases. The genetic alterations which accompany the switch to the angiogenic phenotype are unknown. Discoveries of such genes lead to comprehension of molecular mechanisms of the tumor progression, as well as development of novel therapeutic tools. We have isolated a novel "angiogenic switch molecule", Angiopoietin-2, upregulated specifically in hypervascular hepatocellular carcinoma (HCC). Angiopoietin family proteins have been originally identified to be ligands of vascular endothelial receptor of tyrosine kinase Tie2. Ectopic expression of Angiopoietin-2 promotes the rapid development of human HCCs and produces hemorrhage within tumors in nude mice. These results suggest a role for Angiopoietin-2 in the neovascularization of HCC. In vitro expression of a dominant-negative construct, containing a soluble Tie2 ectodomain (sTie2), led to Angiopoietin protein interaction, inhibition of endogenous Tie2 phosphorylation in vascular endothelial cells. Tumorigenicity with angiogenesis was suppressed by in vivo gene transfer and sTie2 expression in a murine HCC model, suggesting a possible role for Angiopoietin/Tie2 signaling in the induction of HCC neovascularization, and disease progression. More important, inhibition of the Angiopoietin/Tie2 signal transduction cascade is a promising approach for HCC treatment. Furthermore, we have identified two novel genes of the CCN family involved in angiogenesis ; WISP1v (Genbank AB034122) and WISP3v (Genbank AB075040). Gene transfection analysis revealed that WISP1v and WISP3v function as regulators of cell migration. Further analysis should be required to clarify the roles of WISPs in angiogenesis.

在体内进展为恶性肿瘤的特征在于转变为血管生成表型。血管生成开关是肿瘤扩张的关键控制点。肿瘤新生血管化的能力允许肿瘤生长的快速扩张并增加转移的可能性。伴随血管生成表型转换的遗传改变尚不清楚。这些基因的发现导致对肿瘤进展的分子机制的理解，以及新的治疗工具的开发。我们已经分离出一种新的“血管生成开关分子”，血管生成素-2，在富血管肝细胞癌（HCC）中特异性上调。血管生成素家族蛋白最初被鉴定为酪氨酸激酶Tie 2的血管内皮受体的配体。Angiopoietin-2的异位表达促进人肝癌的快速发展并在裸鼠肿瘤内产生出血。这些结果表明血管生成素-2在HCC的新生血管形成中的作用。含有可溶性Tie 2胞外域（sTie 2）的显性阴性构建体的体外表达导致血管生成素蛋白相互作用，抑制血管内皮细胞中的内源性Tie 2磷酸化。在小鼠HCC模型中，通过体内基因转移和sTie 2表达抑制了具有血管生成的致瘤性，这表明血管生成素/Tie 2信号传导在诱导HCC新血管形成和疾病进展中可能起作用。更重要的是，抑制血管生成素/Tie 2信号转导级联是治疗HCC的有希望的方法。此外，我们已经确定了两个新的基因的CCN家族参与血管生成; WISP 1v（Genbank AB 034122）和WISP 3v（Genbank AB 075040）。基因转染分析表明，WISP 1v和WISP 3v作为调节细胞迁移的功能。WISPs在血管生成中的作用有待进一步研究。