Gastric Cancer
Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jul 14, 2006; 12(26): 4130-4136
Published online Jul 14, 2006. doi: 10.3748/wjg.v12.i26.4130
Alphastatin downregulates vascular endothelial cells sphingosine kinase activity and suppresses tumor growth in nude mice bearing human gastric cancer xenografts
Lin Chen, Tao Li, Rong Li, Bo Wei, Zheng Peng
Lin Chen, Tao Li, Rong Li, Bo Wei, Zheng Peng, Department of General Surgery, General Hospital of Chinese PLA, Beijing 100853, China
Author contributions: All authors contributed equally to the work.
Correspondence to: Professor Lin Chen, Department of General Surgery, General Hospital of Chinese PLA, Beijing 100853, China. chenlinbj@vip.sina.com
Telephone: +86-10-66937846 Fax: +86-10-66937846
Received: February 5, 2005
Revised: February 10, 2006
Accepted: February 18, 2006
Published online: July 14, 2006
Abstract

AIM: To investigate whether alphastatin could inhibit human gastric cancer growth and furthermore whether sphingosine kinase (SPK) activity is involved in this process.

METHODS: Using migration assay, MTT assay and Matrigel assay, the effect of alphastatin on vascular endothelial cells (ECs) was evaluated in vitro. SPK and endothelial differentiation gene (EDG)-1, -3, -5 mRNAs were detected by reverse transcription-polymerase chain reaction (RT-PCR). SPK activity assay was used to evaluate the effect of alphastatin on ECs. Matrigel plug assay in nude mice was used to investigate the effect of alphastatin on angiogenesis in vivo. Female nude mice were subcutaneously implanted with human gastric cancer cells (BGC823) for the tumor xenografts studies. Micro vessel density was analyzed in Factor VIII-stained tumor sections by the immunohistochemical SP method.

RESULTS: In vitro, alphastatin inhibited the migration and tube formation of ECs, but had no effect on proliferation of ECs. RT-PCR analysis demonstrated that ECs expressed SPK and EDG-1, -3, -5 mRNAs. In vivo, alphastatin sufficiently suppressed neovascularization of the tumor in the nude mice. Daily administration of alphastatin produced significant tumor growth suppression. Immunohistochemical studies of tumor tissues revealed decreased micro vessel density in alphastatin-treated animals as compared with controls.

CONCLUSION: Downregulating ECs SPK activity may be one of the mechanisms that alphastatin inhibits gastric cancer angiogenesis. Alphastatin might be a useful and relatively nontoxic adjuvant therapy in the treatment of gastric cancer.

Keywords: Stomach neoplasm; Angiogenesis; Endothelial cells; Sphingosine kinase; Cancer therapy