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

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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