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

体内恶性进展的特征是向血管生成表型的转变。血管生成开关是肿瘤生长的关键控制点。肿瘤新生血管的能力允许肿瘤快速生长，并增加转移的可能性。伴随着血管生成表型转变的基因改变尚不清楚。这些基因的发现有助于理解肿瘤进展的分子机制，以及开发新的治疗工具。我们已经分离到一种新的“血管生成开关分子”，血管生成素-2，它在高血管的肝细胞癌(HCC)中特异上调。血管生成素家族蛋白最初被鉴定为酪氨酸激酶Tie2的血管内皮细胞受体的配体。血管生成素-2的异位表达促进了人肝癌的快速发展，并导致裸鼠肿瘤内出血。这些结果提示，血管生成素-2在肝细胞癌的新生血管形成中起作用。在体外表达含有可溶性Tie2胞外区(STie2)的显性-负性结构，导致血管生成素蛋白相互作用，抑制血管内皮细胞内源性Tie2的磷酸化。体内基因转移和sTie2表达抑制了小鼠肝细胞癌模型中血管生成的致瘤性，提示血管生成素/Tie2信号在诱导肝细胞癌新生血管形成和疾病进展中可能发挥作用。更重要的是，抑制血管生成素/Tie2信号转导通路是治疗肝癌的一种有前景的方法。此外，我们在CCN家族中发现了两个与血管生成相关的新基因：WISP1v(Genbank AB034122)和WISP3v(Genbank AB075040)。基因转染分析表明，WISP1v和WISP3v是细胞迁移的调节因子。需要进一步的分析来阐明WISP在血管生成中的作用。

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.