Identification of Angiopoietin-2 as a Novel Angiogenic Switch Molecule of Hepatocellular Carcinoma and Its Signal Inhibitor for Tumor Dormancy Therapy

Shinji Tanaka, Keishi Sugimachi, Yo-ichi Yamashita, Mitsuo Shimada and Keizo Sugimachi

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University

Since the regulation of angiogenic factors induces tumor dormancy, it is urgent to identify target molecules. We cloned an angiogenesis-related factor from human hepatocellular carcinoma, and synthesized the inhibitor of angiogenic signaling. Using targeted differential display, we identified an angiopoietin-2 gene as on of the specific molecules overexpressing in hypervascular hepatocellular carcinoma. Ectopic expression of angiopoietin-2 in nonexpressing hepatocellular carcinoma cells promotes the rapid development of human hepatomas and produces hemorrhage within tumors in nude mice. In vivo gene transfer of Tie2 ectodomain as an inhibitor of angiopoietin suppressed murine hepatocellular carcinoma tumor growth and neovascularization in inoculated mice. These results suggest a role for angiopoietin-2 in the neovascularization of hepatocellular carcinoma. The inhibition of angiopoietin/Tie2 signal transduction is a promising therapeutic application in tumor dormancy therapy.

Key words
Angiopoietin-2, Tie2, hepatocellular carcinoma

Reprint requests
Shinji Tanaka Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University 3-1-1 Maidashi, Fukuoka, 812-8582 JAPAN

Accepted
December 19, 2000

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