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Tie2 vascular endothelial receptor expression and function in hepatocellular carcinoma
Author(s) -
Tanaka Shinji,
Sugimachi Keishi,
Yamashita Yoichi,
Ohga Takefumi,
Shirabe Ken,
Shimada Mitsuo,
Wands Jack R.,
Sugimachi Keizo
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.32535
Subject(s) - angiopoietin receptor , cancer research , neovascularization , angiopoietin , ectodomain , receptor tyrosine kinase , angiogenesis , carcinogenesis , tumor progression , receptor , medicine , biology , vascular endothelial growth factor , cancer , vegf receptors
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.