Colorectal Cancer
Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jan 7, 2006; 12(1): 60-65
Published online Jan 7, 2006. doi: 10.3748/wjg.v12.i1.60
Antithrombin reduces reperfusion-induced hepatic metastasis of colon cancer cells
Masanao Kurata, Kenji Okajima, Toru Kawamoto, Mitsuhiro Uchiba, Nobuhiro Ohkohchi
Masanao Kurata, Toru Kawamoto, Nobuhiro Ohkohchi, Department of Surgery, Functional and Regulatory Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan
Kenji Okajima, Department of Biodefense, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
Mitsuhiro Uchiba, Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
Correspondence to: Nobuhiro Ohkohchi, Department of Surgery, Institute of Clinical Medicine,University of Tsukuba Tennoudai 1-1-1, Tsukuba,Japan. nokochi3@md.tsukuba.ac.jp
Telephone: +81-29-853-3221 Fax: +81-29-853-3222
Received: May 11, 2005
Revised: June 8, 2005
Accepted: June 9, 2005
Published online: January 7, 2006
Abstract

AIM: To examine whether antithrombin (AT) could prevent hepatic ischemia/reperfusion (I/R)-induced hepatic metastasis by inhibiting tumor necrosis factor (TNF)-α-induced expression of E-selectin in rats.

METHODS: Hepatic I/R was induced in rats and mice by clamping the left branches of the portal vein and the hepatic artery. Cancer cells were injected intrasplenically. The number of metastatic nodules was counted on day 7 after I/R. TNF-α and E-selectin mRNA in hepatic tissue, serum fibrinogen degradation products and hepatic tissue levels of 6-keto-PGF, a stable metabolite of PGI2, were measured.

RESULTS: AT inhibited increases in hepatic metastasis of tumor cells and hepatic tissue mRNA levels of TNF-α and E-selectin in animals subjected to hepatic I/R. Argatroban, a thrombin inhibitor, did not suppress any of these changes. Both AT and argatroban inhibited I/R-induced coagulation abnormalities. I/R-induced increases of hepatic tissue levels of 6-keto-PGF were significantly enhanced by AT. Pretreatment with indomethacin completely reversed the effects of AT. Administration of OP-2507, a stable PGI2 analog, showed effects similar to those of AT in this model. Hepatic metastasis in congenital AT-deficient mice subjected to hepatic I/R was significantly increased compared to that observed in wild-type mice. Administration of AT significantly reduced the number of hepatic metastases in congenital AT-deficient mice.

CONCLUSION: AT might reduce I/R-induced hepatic metastasis of colon cancer cells by inhibiting TNF-α-induced expression of E-selectin through an increase in the endothelial production of PGI2. These findings also raise the possibility that AT might prevent hepatic metastasis of tumor cells if administered during the resection of liver tumors.

Keywords: Antithrombin; E-selectin; Hepatic ischemia/reperfusion; Metastasis; Prostacyclin; Tumor necrosis factor-α