Effect of non-anticoagulant N-desulfated heparin on expression of vascular endothelial growth factor, angiogenesis and metastasis of orthotopic implantation of human gastric carcinoma.
OBJECTIVE
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 microL) 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.


CONCLUSIONS
N-desulfated heparin can inhibit metastasis of gastric cancer by suppressing tumor VEGF expression and tumor angiogenesis, but has no obvious anticoagulant activity.
Chen
Jin-Lian
JL
Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China. wqq-021002@163.com
Hong
Jing
J
Lu
Jin-Lai
JL
Chen
Ming-Xiang
MX
Chen
Wei-Xiong
WX
Zhu
Jin-Shui
JS
Chen
Ni-Wei
NW
Chen
Guo-Qiang
GQ
Geng
Jian-Guo
JG
D000818:Animals; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D013274:Stomach Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects*
D042461:Vascular Endothelial Growth Factor A; D006493:Heparin