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Low molecular weight heparin and cancer survival: clinical trials and experimental mechanisms

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Abstract

Introduction

The relationship between cancer and thrombosis is complex, as the hemostatic system is inextricably linked to the mechanisms of cancer growth and metastasis. The coagulation system thus appears to be a site for oncogenic events and necessary for the survival and spread of malignant cells. Although several meta-analyses on the effectiveness of unfractionated heparin and low molecular weight heparin (LMWH) in the treatment of venous thromboembolism (VTE) have suggested a lower mortality risk in cancer patients receiving LMWH, this contention has not received general acceptance. In fact, there exist no sufficiently powered studies to date supporting the routine use of LMWH to improve cancer survival. Meanwhile, the molecular mechanism underlying the anti-neoplastic effect of LMWH which is independent of its anti-coagulant function is largely unexplored and is a topic of active investigation.

Materials and methods

In this communication, we aimed to review comprehensively evidences from clinical trials, meta-analysis as well as experimental molecular research and to identify future research areas of importance so as to stimulate future research on the potential anti-tumor action of LMWH.

Conclusion

Although benefit of LMWH on cancer patients’ survival is controversial depending on the tumor type, cancer stage as well as LMWH type, it appears to be associated with a reduction in VTE and increased bleeding is minor and controllable; thus, randomized controlled trials targeting the survival benefit of certain specific LWMH are needed and justified, and more in-depth experimental researches are imperative to elucidate the anti-tumor effect of anticoagulants.

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Abbreviations

LMWH:

Low molecular weight heparin

UFH:

Unfractionated heparin

VKA:

Vitamin K antagonists

VTE:

Venous thromboembolism

NCCN:

National Comprehensive Cancer Network

ASCO:

American Society of Clinical Oncology

References

  1. Abu Arab W, Kotb R, Sirois M, Rousseau E (2011) Concentration- and time-dependent effects of enoxaparin on human adenocarcinomic epithelial cell line A549 proliferation in vitro. Can J Physiol Pharmacol 89:705–711. doi:10.1139/y11-068

  2. Agnelli G et al (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 10:943–949. doi:10.1016/S1470-2045(09)70232-3

  3. Agnelli G et al (2012) Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 366:601–609. doi:10.1056/NEJMoa1108898

  4. Akl EA et al (2014) Parenteral anticoagulation in ambulatory patients with cancer. Cochrane Database Syst Rev 12:CD006652. doi:10.1002/14651858.CD006652.pub4

  5. Alam F, Chung SW, Hwang SR, Kim JY, Park J, Moon HT, Byun Y (2015) Preliminary safety evaluation of a taurocholate-conjugated low-molecular-weight heparin derivative (LHT7): a potent angiogenesis inhibitor. J Appl Toxicol 35:104–115. doi:10.1002/jat.2995

  6. Altinbas M et al (2004) A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2:1266–1271. doi:10.1111/j.1538-7836.2004.00871.x

  7. Balzarotti M, Fontana F, Marras C, Boiardi A, Croci D, Ciusani E, Salmaggi A (2006) In vitro study of low molecular weight heparin effect on cell growth and cell invasion in primary cell cultures of high-grade gliomas. Oncol Res 16:245–250

  8. Barni S et al (2011) Chemotherapy-associated thromboembolic risk in cancer outpatients and effect of nadroparin thromboprophylaxis: results of a retrospective analysis of the PROTECHT study. J Transl Med 9:179. doi:10.1186/1479-5876-9-179

  9. Bell RG (1978) Vitamin K and chemical carcinogenesis. Lancet 1:1161

  10. Bobek V et al (2005) Anticoagulant drugs increase natural killer cell activity in lung cancer. Lung Cancer 47:215–223. doi:10.1016/j.lungcan.2004.06.012

  11. Carmazzi Y et al (2012) The mechanisms of nadroparin-mediated inhibition of proliferation of two human lung cancer cell lines. Cell Prolif 45:545–556. doi:10.1111/j.1365-2184.2012.00847.x

  12. Che DH, Cao JY, Shang LH, Man YC, Yu Y (2013) The efficacy and safety of low-molecular-weight heparin use for cancer treatment: a meta-analysis. Eur J Intern Med 24:433–439. doi:10.1016/j.ejim.2013.01.006

  13. Collen A, Smorenburg SM, Peters E, Lupu F, Koolwijk P, Van Noorden C, van Hinsbergh VW (2000) Unfractionated and low molecular weight heparin affect fibrin structure and angiogenesis in vitro. Cancer Res 60:6196–6200

  14. Coughlin SR (2005) Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 3:1800–1814. doi:10.1111/j.1538-7836.2005.01377.x

  15. DiPalma JR, McMichael R (1979) The interaction of vitamins with cancer chemotherapy. CA Cancer J Clin 29:280–286

  16. Fluhr H, Seitz T, Zygmunt M (2013) Heparins modulate the IFN-gamma-induced production of chemokines in human breast cancer cells. Breast Cancer Res Treat 137:109–118. doi:10.1007/s10549-012-2334-8

  17. Folkman J, Langer R, Linhardt RJ, Haudenschild C, Taylor S (1983) Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. Science 221:719–725

  18. Fritzsche J, Simonis D, Bendas G (2008) Melanoma cell adhesion can be blocked by heparin in vitro: suggestion of VLA-4 as a novel target for antimetastatic approaches. Thromb Haemost 100:1166–1175

  19. Gialeli C, Theocharis AD, Karamanos NK (2011) Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J 278:16–27. doi:10.1111/j.1742-4658.2010.07919.x

  20. Haas SK et al (2012) Low-molecular-weight heparin versus placebo for the prevention of venous thromboembolism in metastatic breast cancer or stage III/IV lung cancer. Clin Appl Thromb Hemost 18:159–165. doi:10.1177/1076029611433769

  21. Hammond E, Khurana A, Shridhar V, Dredge K (2014) The role of heparanase and sulfatases in the modification of heparan sulfate proteoglycans within the tumor microenvironment and opportunities for novel cancer therapeutics front. Front Oncol 4:195. doi:10.3389/fonc.2014.00195

  22. Handa K, Nudelman ED, Stroud MR, Shiozawa T, Hakomori S (1991) Selectin GMP-140 (CD62; PADGEM) binds to sialosyl-Le(a) and sialosyl-Le(x), and sulfated glycans modulate this binding. Biochem Biophys Res Commun 181:1223–1230

  23. Harvey JR, Mellor P, Eldaly H, Lennard TW, Kirby JA, Ali S (2007) Inhibition of CXCR4-mediated breast cancer metastasis: a potential role for heparinoids? Clin Cancer Res 13:1562–1570. doi:10.1158/1078-0432.CCR-06-1987

  24. Hilgard P, Thornes RD (1976) Anticoagulants in the treatment of cancer. Eur J Cancer 12:755–762

  25. Hostettler N, Naggi A, Torri G, Ishai-Michaeli R, Casu B, Vlodavsky I, Borsig L (2007) P-selectin- and heparanase-dependent antimetastatic activity of non-anticoagulant heparins. FASEB J 21:3562–3572. doi:10.1096/fj.07-8450com

  26. Itoh K, Nakao A, Kishimoto W, Takagi H (1995) Heparin effects on superoxide production by neutrophils. Eur Surg Res 27:184–188

  27. Kakkar AK et al (2004) Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 22:1944–1948. doi:10.1200/JCO.2004.10.002

  28. Klerk CP et al (2005) The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 23:2130–2135. doi:10.1200/JCO.2005.03.134

  29. Kragh M, Binderup L, Vig Hjarnaa PJ, Bramm E, Johansen KB, Frimundt Petersen C (2005) Non-anti-coagulant heparin inhibits metastasis but not primary tumor growth. Oncol Rep 14:99–104

  30. Kuderer NM, Khorana AA, Lyman GH, Francis CW (2007) A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer 110:1149–1161. doi:10.1002/cncr.22892

  31. Lazo-Langner A, Goss GD, Spaans JN, Rodger MA (2007) The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials. J Thromb Haemost 5:729–737. doi:10.1111/j.1538-7836.2007.02427.x

  32. Lean QY, Patel RP, Stewart N, Sohal SS, Gueven N (2014) Identification of pro- and anti-proliferative oligosaccharides of heparins. Integr Biol (Camb) 6:90–99. doi:10.1039/c3ib40206a

  33. Lecumberri R et al (2013) Adjuvant therapy with bemiparin in patients with limited-stage small cell lung cancer: results from the ABEL study. Thromb Res 132:666–670. doi:10.1016/j.thromres.2013.09.026

  34. Lee AY et al (2003) Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146–153. doi:10.1056/NEJMoa025313

  35. Lee AY et al (2005) Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 23:2123–2129. doi:10.1200/JCO.2005.03.133

  36. Li Y, Liu H, Huang YY, Pu LJ, Zhang XD, Jiang CC, Jiang ZW (2013) Suppression of endoplasmic reticulum stress-induced invasion and migration of breast cancer cells through the downregulation of heparanase. Int J Mol Med 31:1234–1242. doi:10.3892/ijmm.2013.1292

  37. Luo CC, Ming YC, Chao HC, Chu SM, Pang ST (2011) Heparin-binding epidermal growth factor-like growth factor downregulates expression of activator protein-1 transcription factor after intestinal ischemia-reperfusion injury. Neonatology 99:241–246. doi:10.1159/000318142

  38. Lyman GH et al (2013) Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 31:2189–2204. doi:10.1200/JCO.2013.49.1118

  39. Ma L, Qiao H, He C, Yang Q, Cheung CH, Kanwar JR, Sun X (2012) Modulating the interaction of CXCR4 and CXCL12 by low-molecular-weight heparin inhibits hepatic metastasis of colon cancer. Invest New Drugs 30:508–517. doi:10.1007/s10637-010-9578-0

  40. Macbeth F et al (2015) Randomized phase III trial of standard therapy plus low molecular weight heparin in patients with lung cancer: FRAGMATIC trial. J Clin Oncol. doi:10.1200/JCO.2015.64.0268

  41. Maraveyas A et al (2012) Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 48:1283–1292. doi:10.1016/j.ejca.2011.10.017

  42. Marchetti M, Vignoli A, Russo L, Balducci D, Pagnoncelli M, Barbui T, Falanga A (2008) Endothelial capillary tube formation and cell proliferation induced by tumor cells are affected by low molecular weight heparins and unfractionated heparin. Thromb Res 121:637–645. doi:10.1016/j.thromres.2007.06.015

  43. Mitroulis I, Kambas K, Anyfanti P, Doumas M, Ritis K (2011) The multivalent activity of the tissue factor-thrombin pathway in thrombotic and non-thrombotic disorders as a target for therapeutic intervention. Expert Opin Ther Targets 15:75–89. doi:10.1517/14728222.2011.532788

  44. Mousa SA (2002) Anticoagulants in thrombosis and cancer: the missing link. Semin Thromb Hemost 28:45–52. doi:10.1055/s-2002-20559

  45. Niu Q, Wang W, Li Y, Ruden DM, Wang F, Song J, Zheng K (2012) Low molecular weight heparin ablates lung cancer cisplatin-resistance by inducing proteasome-mediated ABCG2 protein degradation. PLoS ONE 7:e41035. doi:10.1371/journal.pone.0041035

  46. Norrby K (2006) Low-molecular-weight heparins and angiogenesis. APMIS 114:79–102. doi:10.1111/j.1600-0463.2006.apm_235.x

  47. Ono K et al (2002) 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 86:1803–1812. doi:10.1038/sj.bjc.6600307

  48. Pan Y et al (2011) Role of vimentin in the inhibitory effects of low-molecular-weight heparin on PC-3M cell adhesion to, and migration through, endothelium. J Pharmacol Exp Ther 339:82–92. doi:10.1124/jpet.111.182055

  49. Pelzer U et al (2015) Efficacy of prophylactic low-molecular weight heparin for ambulatory patients with advanced pancreatic cancer: outcomes from the CONKO-004 trial. J Clin Oncol 33:2028–2034. doi:10.1200/JCO.2014.55.1481

  50. Perry JR et al (2010) PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost 8:1959–1965. doi:10.1111/j.1538-7836.2010.03973.x

  51. Phillips PG et al (2011) Increased tumor uptake of chemotherapeutics and improved chemoresponse by novel non-anticoagulant low molecular weight heparin. Anticancer Res 31:411–419

  52. Prandoni P et al (1992) Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 339:441–445

  53. Rema RB, Rajendran K, Ragunathan M (2012) Angiogenic efficacy of Heparin on chick chorioallantoic membrane Vasc. Cell 4:8. doi:10.1186/2045-824X-4-8

  54. Rickles FR, Patierno S, Fernandez PM (2003) Tissue factor, thrombin, and cancer. Chest 124:58S–68S

  55. Riess H et al (2008) Rationale and design of PROSPECT-CONKO 004: a prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy). BMC Cancer 8:361. doi:10.1186/1471-2407-8-361

  56. Sanford D, Naidu A, Alizadeh N, Lazo-Langner A (2014) The effect of low molecular weight heparin on survival in cancer patients: an updated systematic review and meta-analysis of randomized trials. J Thromb Haemost 12:1076–1085. doi:10.1111/jth.12595

  57. Schmitz P et al (2013) Cyr61 is a target for heparin in reducing MV3 melanoma cell adhesion and migration via the integrin VLA-4. Thromb Haemost 110:1046–1054. doi:10.1160/TH13-02-0158

  58. Sideras K et al (2006) Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial. Mayo Clin Proc 81:758–767. doi:10.4065/81.6.758

  59. Sun CC, Qu XJ, Gao ZH (2014) Integrins: players in cancer progression and targets in cancer therapy. Anticancer Drugs 25:1107–1121. doi:10.1097/CAD.0000000000000145

  60. Sylvester DM, Liu SY, Meadows GG (1990) Augmentation of antimetastatic activity of interferon and tumor necrosis factor by heparin. Immunopharmacol Immunotoxicol 12:161–180. doi:10.3109/08923979009019667

  61. Ueda K, Inoue S, Zhang Y, Kutsuna T, Noto K, Arai N, Noguchi M (2009) Heparin induces apoptosis through suppression of AKt in oral squamous cell carcinoma cells. Anticancer Res 29:1079–1088

  62. van Doormaal FF, Di Nisio M, Otten HM, Richel DJ, Prins M, Buller HR (2011) Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer. J Clin Oncol 29:2071–2076. doi:10.1200/JCO.2010.31.9293

  63. Wahlstrom T, Arsenian Henriksson M (2014) Impact of MYC in regulation of tumor cell metabolism. Biochim Biophys Acta. doi:10.1016/j.bbagrm.2014.07.004

  64. Yang G, Yuan J, Li K (2013) EMT transcription factors: implication in osteosarcoma. Med Oncol 30:697. doi:10.1007/s12032-013-0697-2

  65. Yu CJ et al (2010) Effect of Fraxiparine, a type of low molecular weight heparin, on the invasion and metastasis of lung adenocarcinoma A549 cells. Oncol Lett 1:755–760. doi:10.3892/ol_00000132

  66. Zang XP, Nguyen TN, Pento JT (2002) Specific and non-specific KGF inhibition of KGF-induced breast cancer cell motility. Anticancer Res 22:2539–2545

  67. Zwicker JI, Furie BC, Furie B (2007) Cancer-associated thrombosis. Crit Rev Oncol Hematol 62:126–136. doi:10.1016/j.critrevonc.2007.01.001

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Acknowledgments

We gratefully thank Dr. Alejandro Lazo-Langner (University of Western Ontario) for his helpful review of the manuscript. This study was funded by National Natural Science Foundation (81101972; 81272884) and the Canadian Institutes of Health Research (MOP-15691).

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Correspondence to Ning Zhang or Benjamin K. Tsang or Wen Di.

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The authors declare no conflict of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Zhang, N., Lou, W., Ji, F. et al. Low molecular weight heparin and cancer survival: clinical trials and experimental mechanisms. J Cancer Res Clin Oncol 142, 1807–1816 (2016). https://doi.org/10.1007/s00432-016-2131-6

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Keywords

  • Cancer
  • Low molecular weight heparin
  • Survival
  • Randomized trial
  • Molecular mechanisms