Regulation of multiple angiogenic signaling and development of cancer-specific gene therapy

多种血管生成信号的调节和癌症特异性基因治疗的开发

• 批准号: 12671164
• 负责人: TANAKA Shinji
• 金额: $ 2.18万
• 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: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671164/
• 关键词: Angiopoietin; Tie2; hepatocellular carcinoma; angiogenesis; vascular endothelial cell; WISP; CCN; CCN; シグナル伝達

We have previously reported that Angiopoietin (Ang), a ligand for Tie2 vascular endothelial-specific receptor tyrosine kinase, may play a role in the progression of human hepatocellular carcinoma (HCC) is generally characterized as a hypervascular tumor of rapid growth (J Clin Invest 1999) and matrix proteinase expression (Cancer Res 2001). However, the role of Tie2 receptor in hepatic oncogenesis is unknown. The Tie2 receptor protein was overexpressed in the neovascular endothelium of 31/39 (80%) human HCC tumors by immunohistochemical analysis with significant correlation to cell dedifferentiation and tumor size (p<0.05). In vitro expression of a dominant-negative construct, containing a soluble Tie2 ectodomain (sTie2), led to Ang protein interaction, inhibition of endogeneous Tie2 phosphorylation in vascular endothelial cells, and matrix metalloproteinase-9 (MMP-9) suppression. Tumorigenicity with neovascularization was suppressed by in vivo gene transfer and sTie2 expression in a m … More urine HCC model suggesting a possible role for Tie2 expression in the induction of HCC neovascularization, and disease progression (Hepatology (in press)). More important, inhibition of the Ang/Tie2 signal transduction cascade is a promising approach for tumor treatment.Using targeted differential displays, we identified a novel variant of the CCN family member WISP1 (Wnt-induced secreted protein 1), named WISP1v, as overexpressed in scirrhous gastric carcinomas. Members of the emerging family of the CCN gene (for connective tissue growth factor, cysteine-rich 61, nephroblastoma overexpressed) encode cysteine-rich secreted proteins with roles in human fibrotic disorders and cancer angiogenesis. Predicted protein of the WISP1 v completely lacks a module of Von Willebrand type C that is thought to participate in protein complex formation. Ectopic expression revealed WISP1 v to be a secreted oncoprotein inducing a striking cellular transformation and rapid piling-up growth. It is noteworthy that WISP1 v transfectants enhanced the invasive phenotype of co-cultured gastric carcinoma cells, while wild-type WISP1 had no such potential. These findings suggest that CCN protein WISP1 v is involved in the aggressive progression of scirrhous gastric carcinoma. Less

我们之前报道过，血管生成素 (Ang) 是 Tie2 血管内皮特异性受体酪氨酸激酶的配体，可能在人肝细胞癌 (HCC) 的进展中发挥作用，其一般特征为快速生长的富血管肿瘤 (J Clin Invest 1999) 和基质蛋白酶表达 (Cancer Res 2001)。然而，Tie2受体在肝肿瘤发生中的作用尚不清楚。通过免疫组织化学分析，Tie2 受体蛋白在 31/39 (80%) 人 HCC 肿瘤的新生血管内皮中过度表达，与细胞去分化和肿瘤大小显着相关 (p<0.05)。含有可溶性 Tie2 胞外域 (sTie2) 的显性失活构建体的体外表达导致 Ang 蛋白相互作用、血管内皮细胞内源性 Tie2 磷酸化的抑制以及基质金属蛋白酶 9 (MMP-9) 的抑制。体内基因转移和尿 HCC 模型中的 sTie2 表达抑制了新生血管形成的致瘤性，这表明 Tie2 表达在诱导 HCC 新生血管和疾病进展中可能发挥作用（肝病学（正在出版））。更重要的是，抑制Ang/Tie2信号转导级联是一种有前途的肿瘤治疗方法。利用靶向差异显示，我们鉴定了CCN家族成员WISP1（Wnt诱导的分泌蛋白1）的一种新变体，命名为WISP1v，在硬质胃癌中过度表达。 CCN 基因新兴家族的成员（结缔组织生长因子、富含半胱氨酸 61、肾母细胞瘤过度表达）编码富含半胱氨酸的分泌蛋白，在人类纤维化疾病和癌症血管生成中发挥作用。 WISP1 v 的预测蛋白完全缺乏被认为参与蛋白质复合物形成的 Von Willebrand C 型模块。异位表达揭示 WISP1 v 是一种分泌性癌蛋白，可诱导显着的细胞转化和快速堆积生长。值得注意的是，WISP1 v 转染子增强了共培养胃癌细胞的侵袭表型，而野生型 WISP1 则没有这种潜力。这些发现表明CCN蛋白WISP1 v参与了硬质胃癌的侵袭性进展。较少的

项目成果

Tanaka S, Sugimachi K, Saeki H, Kinoshita J, Ohga T, Shimada M, Maehara Y, Sugimachi K: "A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in cirrhous gastric carcinoma"Oncogene. 20(39). 5525-32 (2001)

Tanaka S、Sugimachi K、Saeki H、Kinoshita J、Ohga T、Shimada M、Maehara Y、Sugimachi K：“缺乏 Von Willebrand C 型模块的 WISP1 的新型变体，在肝硬化胃癌中过度表达”癌基因。

Yamashita Yi, Hamatsu T, Rikimaru T, Tanaka S, Shirabe K, Shimada M, Sugimachi K: "Bile Leakage After Hepatic Resection"Annals of Surgery. 233(1). 45-50 (2001)

Yamashita Yi、Hamatsu T、Rikimaru T、Tanaka S、Shirabe K、Shimada M、Sugimachi K：“肝切除术后胆漏”外科年鉴。

Tanaka S, Sugimachi K, Kawaguchi H, Saeki H, Ohno S, Wands JR, Sugimachi K: "Grb7 signal transduction protein mediates metastatic progression of esopahgeal carcinoma"Journal of Cellular Physiology. 183(3). 411-415 (2000)

Tanaka S、Sugimachi K、Kawaguchi H、Saeki H、Ohno S、Wands JR、Sugimachi K：“Grb7 信号转导蛋白介导食管癌的转移进展”细胞生理学杂志。

Shimada M, Hashizume M, Maehara S, Tsujita E, Rikimaru T, Yamashita Y, Tanaka S, Adachi E, Sugimachi K: "Laparoscopic hepatectomy for hepatocellular carcinoma"Surgical Encoscopy. 15. 541-4 (2001)

Shimada M、Hashizume M、Maehara S、Tsujita E、Rikimaru T、Yamashita Y、Tanaka S、Adachi E、Sugimachi K：“肝细胞癌的腹腔镜肝切除术”外科内窥镜检查。

Sugimachi K, Maehara S, Tanaka S, Shimada M, Sugimachi K: "Repeat hepatectomy is the most useful treatment for recurrent hepatocellular carcinoma"Journal of Hepatobiliary Pancreatic Surgery. 8(5). 410-6 (2001)

Sugimachi K、Maehara S、Tanaka S、Shimada M、Sugimachi K：“重复肝切除术是复发性肝细胞癌最有效的治疗方法”《肝胆胰外科杂志》。