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World J Gastroenterol. Jan 21, 2007; 13(3): 457-461
Published online Jan 21, 2007. doi: 10.3748/wjg.v13.i3.457
Effect of non-anticoagulant N-desulfated heparin on expression of vascular endothelial growth factor, angiogenesis and metastasis of orthotopic implantation of human gastric carcinoma
Jin-Lian Chen, Jing Hong, Jin-Lai Lu, Ming-Xiang Chen, Wei-Xiong Chen, Jin-Shui Zhu, Ni-Wei Chen, Guo-Qiang Chen, Jian-Guo Geng
Jin-Lian Chen, Jing Hong, Jin-Lai Lu, Ming-Xiang Chen, Wei-Xiong Chen, Jin-Shui Zhu, Ni-Wei Chen, Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China
Guo-Qiang Chen, Shanghai Laboratory Animal Center, Chinese Academy of Sciences, Shanghai 200031, China
Jian-Guo Geng, Shanghai Institute of Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China
Author contributions: All authors contributed equally to the work.
Supported by the Scientific Foundation of Shanghai Public Health Administration, No. 034045
Correspondence to: Jin-Lian Chen, Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China. wqq-021002@163.com
Telephone: +86-21-64369181 Fax: +86-21-64369181
Received: October 13, 2006
Revised: November 15, 2006
Accepted: December 4, 2006
Published online: January 21, 2007
Abstract

AIM: To investigate the effect of N-desulfated heparin on tumor metastasis and angiogenesis, and expression of vascular endothelial growth factor (VEGF) of orthotopic implantation of human gastric carcinoma in male severe combined immune deficiency (SCID) mice.

METHODS: Human gastric cancer SGC-7901 cells were orthotopically implanted into the stomach of SCID mice. The mice were randomly divided into normal saline group and N-desulfated heparin group. One week after operation, the mice in N-desulfated heparin group received i.v. injections of N-desulfated heparin (Shanghai Institute of Cell Biology, Chinese Academy of Sciences, 10 mg/kg.d) twice weekly for 3 wk. The mice in normal saline group received i.v. injections of normal saline (100 μL) twice weekly for 3 wk. The mice were sacrificed six weeks after implantation. Tumor metastasis was evaluated histologically for metastasis under microscope. Intratumoral microvessel density (MVD) and VEGF expression were evaluated immuohistochemically. VEGF mRNA expression in gastric tissue of SCID mice was detected by real time PCR.

RESULTS: The tumor metastasis rate was 80% in normal saline group and 20% in N-desulfated heparin group (P < 0.05). MVD was 8.0 ± 3.1 in normal saline group and 4.3 ± 1.8 in N-desulfated heparin group (P < 0.05). VEGF positive immunostaining was found in cytoplasm of cancer cells. The rate of VEGF positive expression was higher in normal saline group than in N-desulfated heparin treated group (90% vs 20%, P < 0.05). VEGF mRNA expression was significantly inhibited by N-desulfated heparin and was higher in normal saline group than in N-desulfated heparin group (Ct value 19.51 ± 1.01 vs 22.55 ± 1.36, P < 0.05). N-desulfated heparin significantly inhibited the expression of VEGF mRNA in cancer cells. No bleeding occurred in N-desulfated heparin group.

CONCLUSION: N-desulfated heparin can inhibit metastasis of gastric cancer by suppressing tumor VEGF expression and tumor angiogenesis, but has no obvious anticoagulant activity.

Keywords: N-desulfated heparin, Gastric carcinoma, Metastasis, Tumor angiogenesis, Vascular endothelial growth factor