Inhibitory effect of non-anticoagulant heparin (S-NACH) on pancreatic cancer cell adhesion and metastasis in human umbilical cord vessel segment and in mouse model
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Metastasis is the most devastating aspect of cancer and it is the main cause of morbidity and mortality in cancer patients. Tumor cell adhesion to the vascular endothelial cell lining is an important step in metastatic progression and is prompted by platelets. Mucin 1 is over-expressed and aberrantly glycosylated in more than 60% of pancreatic ductal adeno-carcinomas, which mediate adhesion of pancreatic cancer cells to platelets via P-selectin. The anticoagulant low molecular weight heparins (LMWHs), which are commonly used in venous Thromboprophylaxis and treatment, appear to have an effect on cancer survival. The aim of this study is to investigate the effect of platelets on human pancreatic cancer MPanc96 cell adhesion to the endothelial cell vessel wall, and to examine the effect of heparin derivatives on MPanc96 adhesion using a novel, in vitro model of human umbilical cord vein. The modified heparin S-NACH (sulfated non-anticoagulant heparin), which is devoid of antithrombin (AT) binding and devoid of inhibition of systemic AT-dependent coagulation factors such as factor Xa and IIa, and the LMWH tinzaparin both potently reduced adhesion and invasion of fluorescence-labeled MPanc96 cancer cells to the endothelial layer of umbilical cord vein in a dose-dependent manner. S-NACH effectively inhibited P-selectin mediated MPanc96 cell adhesion, and inhibited cell adhesion and invasion similar to tinzaparin, indicating that systemic anticoagulation is not a necessary component for heparin attenuation of cancer cell adhesion, invasion, and metastasis. Also, S-NACH and tinzaparin versus unfractionated heparin, heparin derivatives enoxaparin, deltaparin, fraxiparin, and fondaparinux were evaluated for their effect on platelet-cancer cell adhesion. An in vivo anti-metastatic S-NACH-treated nude mouse model of MPanc96 pancreatic cancer cell metastasis demonstrated potent anti-metastasis efficacy as evidenced by IVIS imaging and histological staining.
KeywordsHeparin Low molecular weight heparin Anticoagulant Heparin derivatives P-selectin glycoprotein ligand-1 P-selectin Platelet Endothelial cells Cancer cell adhesion Invasion Metastasis
This work was supported by NIH grant R21 CA124931. We thank Dr. Howard Smith of Albany Medical College for his assistance with the IRB approval process and continuous support. We appreciate the excellent editing by Dr. Kelly Keating and the technical support by members of the Pharmaceutical Research Institute, Rensselaer, NY.
- 4.Zhang N, Zhang WJ, Cai HQ, Liu HL, Peng L, Li CH, Ye LY, Xu SQ, Yang ZH, Lou JN (2011) Platelet adhesion and fusion to endothelial cell facilitate the metastasis of tumor cell in hypoxia-reoxygenation condition. Clin Exp Metastasis 28(1):1–12. doi: 10.1007/s10585-010-9353-9 PubMedCrossRefGoogle Scholar
- 9.Icli F, Akbulut H, Utkan G, Yalcin B, Dincol D, Isikdogan A, Demirkazik A, Onur H, Cay F, Buyukcelik A (2007) Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer. J Surg Oncol 95(6):507–512. doi: 10.1002/jso.20728 PubMedCrossRefGoogle Scholar
- 17.Klerk CP, Smorenburg SM, Otten HM, Lensing AW, Prins MH, Piovella F, Prandoni P, Bos MM, Richel DJ, van Tienhoven G, Buller HR (2005) The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 23(10):2130–2135. doi: 10.1200/JCO.2005.03.134 PubMedCrossRefGoogle Scholar
- 18.Agnelli G, Gussoni G, Bianchini C, Verso M, Mandala M, Cavanna L, Barni S, Labianca R, Buzzi F, Scambia G, Passalacqua R, Ricci S, Gasparini G, Lorusso V, Bonizzoni E, Tonato M (2009) Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 10(10):943–949. doi: 10.1016/S1470-2045(09)70232-3 PubMedCrossRefGoogle Scholar
- 19.von Delius S, Ayvaz M, Wagenpfeil S, Eckel F, Schmid RM, Lersch C (2007) Effect of low-molecular-weight heparin on survival in patients with advanced pancreatic adenocarcinoma. Thromb Haemost 98(2):434–439Google Scholar
- 20.Maraveyas A, Ettelaie C, Echrish H, Li C, Gardiner E, Greenman J, Madden LA (2010) Weight-adjusted dalteparin for prevention of vascular thromboembolism in advanced pancreatic cancer patients decreases serum tissue factor and serum-mediated induction of cancer cell invasion. Blood Coagul Fibrinolysis 21(5):452–458. doi: 10.1097/MBC.0b013e328338dc49 PubMedCrossRefGoogle Scholar
- 25.Yoshitomi Y, Nakanishi H, Kusano Y, Munesue S, Oguri K, Tatematsu M, Yamashina I, Okayama M (2004) Inhibition of experimental lung metastases of Lewis lung carcinoma cells by chemically modified heparin with reduced anticoagulant activity. Cancer Lett 207(2):165–174. doi: 10.1016/j.canlet.2003.11.037 PubMedCrossRefGoogle Scholar
- 26.Borsig L, Wong R, Hynes RO, Varki NM, Varki A (2002) Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc Natl Acad Sci U S A 99(4):2193–2198. doi: 10.1073/pnas.261704098 PubMedCrossRefGoogle Scholar
- 28.Lapierre F, Holme K, Lam L, Tressler RJ, Storm N, Wee J, Stack RJ, Castellot J, Tyrrell DJ (1996) Chemical modifications of heparin that diminish its anticoagulant but preserve its heparanase-inhibitory, angiostatic, anti-tumor and anti-metastatic properties. Glycobiology 6(3):355–366PubMedCrossRefGoogle Scholar
- 31.Besmer DM, Curry JM, Roy LD, Tinder TL, Sahraei M, Schettini J, Hwang SI, Lee YY, Gendler SJ, Mukherjee P (2011) Pancreatic ductal adenocarcinoma mice lacking mucin 1 have a profound defect in tumor growth and metastasis. Cancer Res 71(13):4432–4442. doi: 10.1158/0008-5472.CAN-10-4439 PubMedCrossRefGoogle Scholar