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

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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.