What are possibility that REGN discover class molecules which will inhibit binding of he Ang-1,2 or to TIE-2 receptor(s)?
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Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma
Shinji Tanaka1, Masaki Mori1, Yoshihiro Sakamoto2, Masatoshi Makuuchi2, Keizo Sugimachi3 and Jack R. Wands4
1 Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu 874-0838, Japan 2 Department of Surgery, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan 3 Department of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka 814-8582, Japan 4 Molecular Hepatology Laboratory, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
Address correspondence to: Shinji Tanaka, Department of Surgery, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumibaru, Beppu 874-0838, Japan. Phone: 81-977-27-1650; Fax: 81-977-27-1651; E-mail: shinji@tsurumi.beppu.kyushu-u.ac.jp
Received for publication August 12, 1998, and accepted in revised form December 7, 1998.
Human hepatocellular carcinoma (HCC) is generally a highly vascular tumor, but the mechanisms of neovascularization that permit rapid growth have not been defined. Angiopoietins (Ang) recently have been identified as ligands for vascular endothelial-specific Tie2 receptor tyrosine kinase and may be important growth factors in the generation of new blood vessels. We investigated Ang expression in 23 samples of HCC and paired adjacent uninvolved liver samples to determine if these genes have a potential role in the growth and spread of this disease. The full coding sequence of a variant angiopoietin-2 (Ang2) cDNA was obtained from HCC specimens, and the biologic consequences of overexpression on tumor formation and hemorrhage were determined in an animal model system. Angiopoietin-1 (Ang1) was equally expressed in HCC and adjacent noncarcinomatous liver tissue. Surprisingly, Ang2 was found to be highly expressed only in tumor tissue. In addition, Ang2 was expressed in 10 of 12 hypervascular HCC, but only in 2 of 11 hypovascular HCC. Ectopic expression of Ang2 in nonexpressing HCC cells promotes the rapid development of human hepatomas and produces hemorrhage within tumors in nude mice. These results suggest a role for Ang2 in the neovascularization of HCC. This enhanced gene expression may contribute to the clinical hypervascular phenotype, as well as tumor formation and progression. |
