Effect of Non-anticoagulant N-desulfated Heparin on Expression of Vascular Endothelial Growth Factor, Angiogenesis and Metastasis of Orthotopic Implantation of Human Gastric Carcinoma

Overview

Journal World J Gastroenterol

Publisher Baishideng Publishing Group

Specialty Gastroenterology

Date 2007 Jan 19

PMID 17230619

Citations 4

Authors

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

Affiliations

Soon will be listed here.

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 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.

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

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References

Chen J, Chen W, Zhu J, Chen N, Zhou T, Yao M . Effect of P-selectin monoclonal antibody on metastasis of gastric cancer and immune function. World J Gastroenterol. 2003; 9(7):1607-10. PMC: 4615516. DOI: 10.3748/wjg.v9.i7.1607. View

Shinkaruk S, Bayle M, Lain G, Deleris G . Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy. Curr Med Chem Anticancer Agents. 2003; 3(2):95-117. DOI: 10.2174/1568011033353452. View

Fondevila C, Metges J, Fuster J, Grau J, Palacin A, Castells A . p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer. 2004; 90(1):206-15. PMC: 2395306. DOI: 10.1038/sj.bjc.6601455. View

Ranieri G, Coviello M, Chiriatti A, Stea B, Montemurro S, Quaranta M . Vascular endothelial growth factor assessment in different blood fractions of gastrointestinal cancer patients and healthy controls. Oncol Rep. 2004; 11(2):435-9. View

Mousa S . Low-molecular-weight heparin in thrombosis and cancer. Semin Thromb Hemost. 2004; 30 Suppl 1:25-30. DOI: 10.1055/s-2004-823000. View

Bobek V, Kovarik J . Antitumor and antimetastatic effect of warfarin and heparins. Biomed Pharmacother. 2004; 58(4):213-9. DOI: 10.1016/j.biopha.2003.11.007. View

Tsujitani S, Saito H, Maeta Y, Yamaguchi K, Tatebe S, Kondo A . Neoangiogenesis in patients with gastric carcinoma in relation to the expression of vascular endothelial growth factor and thymidine phosphorylase. Anticancer Res. 2004; 24(3b):1853-9. View

Mousa S, Mohamed S . Anti-angiogenic mechanisms and efficacy of the low molecular weight heparin, tinzaparin: anti-cancer efficacy. Oncol Rep. 2004; 12(4):683-8. View

Tovari J, Bereczky B, Gilly R, Skopal J, Vago A, Timar J . [Heparin inhibits metastatization of experimental melanoma]. Magy Onkol. 2004; 48(3):235-41. DOI: HUON.2004.48.3.0235. View

10.

Pisano C, Aulicino C, Vesci L, Casu B, Naggi A, Torri G . Undersulfated, low-molecular-weight glycol-split heparin as an antiangiogenic VEGF antagonist. Glycobiology. 2004; 15(2):1C-6C. DOI: 10.1093/glycob/cwi007. View

11.

Castelli R, Porro F, Tarsia P . The heparins and cancer: review of clinical trials and biological properties. Vasc Med. 2005; 9(3):205-13. DOI: 10.1191/1358863x04vm566ra. View

12.

Naggi A, Casu B, Perez M, Torri G, Cassinelli G, Penco S . Modulation of the heparanase-inhibiting activity of heparin through selective desulfation, graded N-acetylation, and glycol splitting. J Biol Chem. 2005; 280(13):12103-13. DOI: 10.1074/jbc.M414217200. View

13.

Klerk C, Smorenburg S, Otten H, Lensing A, Prins M, Piovella F . The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005; 23(10):2130-5. DOI: 10.1200/JCO.2005.03.134. View

14.

Kragh M, Binderup L, Vig Hjarnaa P, Bramm E, Johansen K, Frimundt Petersen C . Non-anti-coagulant heparin inhibits metastasis but not primary tumor growth. Oncol Rep. 2005; 14(1):99-104. View

15.

Petralia G, Lemoine N, Kakkar A . Mechanisms of disease: the impact of antithrombotic therapy in cancer patients. Nat Clin Pract Oncol. 2005; 2(7):356-63. DOI: 10.1038/ncponc0225. View

16.

Szende B, Paku S, Racz G, Kopper L . Effect of Fraxiparine and heparin on experimental tumor metastasis in mice. Anticancer Res. 2005; 25(4):2869-72. View

17.

Jung Y, Mansfield P, Akagi M, Takeda A, Liu W, Bucana C . Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer. 2002; 38(8):1133-40. DOI: 10.1016/s0959-8049(02)00013-8. View

18.

Kakeji Y, Koga T, Sumiyoshi Y, Shibahara K, Oda S, Maehara Y . Clinical significance of vascular endothelial growth factor expression in gastric cancer. J Exp Clin Cancer Res. 2002; 21(1):125-9. View

19.

Ono K, Ishihara M, Ishikawa K, Ozeki Y, Deguchi H, Sato M . Periodate-treated, non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) affects angiogenesis and inhibits subcutaneous induced tumour growth and metastasis to the lung. Br J Cancer. 2002; 86(11):1803-12. PMC: 2375397. DOI: 10.1038/sj.bjc.6600307. View

20.

Zacharski L . Anticoagulants in cancer treatment: malignancy as a solid phase coagulopathy. Cancer Lett. 2002; 186(1):1-9. DOI: 10.1016/s0304-3835(02)00258-6. View