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

我们先前已经报道，血管生成素(Ang)是Tie2血管内皮细胞特异性受体酪氨酸激酶的配体，可能在人肝细胞癌的发展过程中发挥作用(J Clin Invest 1999)和基质蛋白水解酶的表达(癌症RES 2001)。然而，Tie2受体在肝肿瘤发生中的作用尚不清楚。免疫组织化学分析显示，Tie2受体蛋白在31/39(80%)人肝细胞癌新生血管内皮细胞中过表达，且与细胞去分化和肿瘤大小显著相关(p&lt；0.05)。在体外，含有可溶性Tie2胞外区(STie2)的显性-负性结构域的表达导致Ang蛋白相互作用，抑制血管内皮细胞内源性Tie2磷酸化，并抑制基质金属蛋白酶-9(MMP9)。通过体内基因转移和m-…中sTie2的表达抑制新生血管的致瘤性更多的尿液肝癌模型表明Tie2的表达可能在诱导肝癌新生血管和疾病进展中发挥作用(肝病学正在出版)。更重要的是，抑制Ang/Tie2信号转导通路是治疗肿瘤的一种有前景的方法。利用靶向差异显示，我们发现了CCN家族成员WISP1(Wnt诱导的分泌蛋白1)的一个新的变体，命名为WISP1v，在硬化性胃癌中过表达。CCN基因是新近出现的CCN基因家族成员(代表结缔组织生长因子，富含半胱氨酸的61，肾母细胞瘤)，编码富含半胱氨酸的分泌蛋白，在人类纤维化疾病和肿瘤血管生成中起作用。预测的WISP1v蛋白完全缺乏一个被认为参与蛋白质复合体形成的Von Willebrand C型模块。异位表达表明WISP1v是一种分泌型癌蛋白，可诱导细胞转化和快速堆积生长。值得注意的是，WISP1v转基因细胞增强了共培养的胃癌细胞的侵袭表型，而野生型WISP1没有这种潜力。这些发现提示CCN蛋白WISP1v参与了硬化性胃癌的侵袭性进展。较少

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