Tie2 vascular endothelial receptor expression and function in hepatocellular carcinoma

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Abstract
Hepatocellular carcinoma (HCC) is generally characterized as a hypervascular tumor of rapid growth. 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 HCC (J Clin Invest 1999;103:341-345) and matrix proteinase expression (Cancer Res 2001;61:2145-2153). However, the role of Tie2 receptor in hepatic oncogenesis is unknown. The Tie2 receptor protein was overexpressed in the neovascular endothelium of 31 of 39 (80%) human HCC tumors by immunohistochemical analysis with significant correlation to cell dedifferentiation and tumor size (P < .05). In vitro expression of a dominant-negative construct, containing a soluble Tie2 ectodomain (sTie2), led to Ang protein interaction, inhibition of endogenous Tie2 phosphorylation in vascular endothelial cells and matrix metalloproteinase 9 (MMP-9) suppression. In conclusion, tumorigenicity with neovascularization was suppressed by in vivo gene transfer and sTie2 expression in a murine HCC model, suggesting a possible role for Tie2 expression in the induction of HCC neovascularization and disease progression. Inhibition of the Ang/Tie2 signal transduction cascade is a promising approach for tumor treatment.
Funding Information
  • Fukuoka Cancer Association
  • Ichiro Kanehara Foundation
  • Uehara Memorial Foundation
  • Mochida Memorial Foundation
  • Kaibara Morikazu Research Fund
  • Kanae Foundation
  • Ministry of Education, Science, Sports, and Culture of Japan
  • National Institutes of Health, Bethesda, MD (CA 35711)
  • Japan Cancer Society Incitement Award