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Ticagrelor inhibits platelet–tumor cell interactions and metastasis in human and murine breast cancer

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Abstract

Activated platelets promote the proliferation and metastatic potential of cancer cells. Platelet activation is largely mediated through ADP engagement of purinergic P2Y12 receptors on platelets. We examined the potential of the reversible P2Y12 inhibitor ticagrelor, an agent used clinically to prevent cardiovascular and cerebrovascular events, to reduce tumor growth and metastasis. In vitro, MCF-7, MDA-MB-468, and MDA-MB-231 human mammary carcinoma cells exhibited decreased interaction with platelets treated with ticagrelor compared to untreated platelets. Prevention of tumor cell–platelet interactions through pretreatment of platelets with ticagrelor did not improve natural killer cell-mediated tumor cell killing of K562 myelogenous leukemia target cells. Additionally, ticagrelor had no effect on proliferation of 4T1 mouse mammary carcinoma cells co-cultured with platelets, or on primary 4T1 tumor growth. In an orthotopic 4T1 breast cancer model, ticagrelor (10 mg/kg), but not clopidogrel (10 mg/kg) or saline, resulted in reduced metastasis and improved survival. Ticagrelor treatment was associated with a marked reduction in tumor cell–platelet aggregates in the lungs at 10, 30 and 60 min post-intravenous inoculation. These findings suggest a role for P2Y12-mediated platelet activation in promoting metastasis, and provide support for the use of ticagrelor in the prevention of breast cancer spread.

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References

  1. Mammadova-Bach E, Zigrino P, Brucker C, Bourdon C, Freund M, De Arcangelis A et al (2016) Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell-derived ADAM9. JCI Insight 1:e88245

    Article  PubMed  PubMed Central  Google Scholar 

  2. Leblanc R, Peyruchaud O (2016) Metastasis: new functional implications of platelets and megakaryocytes. Blood 128:24–31

    Article  CAS  PubMed  Google Scholar 

  3. Miyashita T, Tajima H, Makino I, Nakagawara H, Kitagawa H, Fushida S et al (2015) Metastasis-promoting role of extravasated platelet activation in tumor. J Surg Res 193:289–294

    Article  CAS  PubMed  Google Scholar 

  4. Wang Y, Sun Y, Li D, Zhang L, Wang K, Zuo Y et al (2013) Platelet P2Y12 is involved in murine pulmonary metastasis. PLoS ONE 8:e80780

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kerr BA, McCabe NP, Feng W, Byzova TV (2013) Platelets govern pre-metastatic tumor communication to bone. Oncogene 32:4319–4324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cooke NM, Spillane CD, Sheils O, O’Leary J, Kenny D (2015) Aspirin and P2Y12 inhibition attenuate platelet-induced ovarian cancer cell invasion. BMC Cancer 15:627

    Article  PubMed  PubMed Central  Google Scholar 

  7. Guillem-Llobat P, Dovizio M, Bruno A, Ricciotti E, Cufino V, Sacco A et al (2016) Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells. Oncotarget 7:32462–32477

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gebremeskel S, LeVatte T, Liwski RS, Johnston B, Bezuhly M (2015) The reversible P2Y12 inhibitor ticagrelor inhibits metastasis and improves survival in mouse models of cancer. Int J Cancer 136:234–240

    Article  CAS  PubMed  Google Scholar 

  9. Labelle M, Begum S, Hynes ROO (2011) Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20:576–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nieswandt B, Hafner M, Echtenacher B, Männel DN (1999) Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 59:1295–1300

    CAS  PubMed  Google Scholar 

  11. Palumbo JS, Talmage KE, Massari JV et al (2005) Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 105:178–185

    Article  CAS  PubMed  Google Scholar 

  12. Stegner D, Dutting S, Nieswandt B (2014) Mechanistic explanation for platelet contribution to cancer metastasis. Thromb Res 133:S149–S157

    Article  CAS  PubMed  Google Scholar 

  13. Li R, Ren M, Chen N, Luo M, Deng X, Xia J et al (2014) Presence of intratumoral platelets is associated with tumor vessel structure and metastasis. BMC Cancer 14:167

    Article  PubMed  PubMed Central  Google Scholar 

  14. Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z (2012) Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 379:1591–1601

    Article  CAS  PubMed  Google Scholar 

  15. Algra AM, Rothwell PM (2012) Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol 13:518–527

    Article  CAS  PubMed  Google Scholar 

  16. Gachet C (2008) P2 receptors, platelet function and pharmacological implications. Thromb Haemost 99:466–472

    Article  CAS  PubMed  Google Scholar 

  17. Cho MS, Noh K, Haemmerle M, Li D, Park H, Hu Q, Hisamatsu T, Mitamura T, Mak SLC, Kunapuli S, Ma Q, Sood AK, Afshar-Kharghan V (2017) Role of ADP receptors on platelets in the growth of ovarian cancer. Blood. https://doi.org/10.1182/blood-2017-02-769893

    PubMed Central  Google Scholar 

  18. Wallentin L, Becker RC, Budaj A et al (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057

    Article  CAS  PubMed  Google Scholar 

  19. Preusch MR, Rusnak J, Staudacher K, Mogler C, Uhlmann L, Sievers P, Bea F, Katus HA, Blessing E, Staudacher I (2016) Ticagrelor promotes atherosclerotic plaque stability in a mouse model of advanced atherosclerosis. Drug Des Dev Ther 10:2691–2699

    Article  CAS  Google Scholar 

  20. Ye Y, Birnbaum GD, Perez-Polo JR, Nanhwan MK, Nylander S, Birnbaum Y (2015) Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. Arterioscler Thromb Vasc Biol 35:1805–1814

    Article  CAS  PubMed  Google Scholar 

  21. Lelekakis M, Moseley JM, Martin TJ, Hards D, Williams E, Ho P, Lowen D, Javni J, Miller JR, Slavin J, Anderson RL (1999) A novel orthotopic model of breast cancer metastasis to bone. Clin Exp Metastasis 17:163–170

    Article  CAS  PubMed  Google Scholar 

  22. Holliday DL, Speirs V (2011) Choosing the right cell line for breast cancer research. Breast Cancer Res 13:215. https://doi.org/10.1186/bcr2889

    Article  PubMed  PubMed Central  Google Scholar 

  23. Coupland LA, Chong BH, Parish CR (2012) Platelets and P-selectin control tumor cell metastasis in an organ-specific manner and independently of NK cells. Cancer Res 72:4662–4671

    Article  CAS  PubMed  Google Scholar 

  24. Aigner S, Ramos CL, Hafezi-Moghadam A, Lawrence MB, Friederichs J, Altevogt P, Ley K (1998) CD24 mediates rolling of breast carcinoma cells on P-selectin. FASEB J 12:1241–1251

    Article  CAS  PubMed  Google Scholar 

  25. Nasti TH, Bullard DC, Yusuf N (2015) P-selectin enhances growth and metastasis of mouse mammary tumors by promoting regulatory T cell infiltration into the tumors. Life Sci 131:11–18

    Article  CAS  PubMed  Google Scholar 

  26. Stone JP, Wagner DD (1993) P-selectin mediates adhesion of platelets to neuroblastoma and small cell lung cancer. J Clin Invest 92:804–813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Berg M, Lundqvist A, McCoy P, Samsel L, Fan Y, Tawab A et al (2009) Clinical grade ex vivo-expanded human natural killer cells upregulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells. Cytotherapy 11:341–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lim SA, Kim TJ, Lee JE, Sonn CH, Kim K, Kim J et al (2013) Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. Cancer Res 73:2598–2607

    Article  CAS  PubMed  Google Scholar 

  29. Kim E, Ahn Y-O, Kim S, Kim TM, Keam B, Heo DS (2012) Ex vivo activation and expansion of natural killer cells from advanced cancer patients with feeder cells from healthy volunteers. Cancer Res 72:3514

    Article  Google Scholar 

  30. Luhm J, Brand J-M, Koritke P, Höppner M, Kirchner H, Frohn C (2002) Large-scale generation of natural killer lymphocytes for clinical application. J Hematother Stem Cell Res 11:651–657

    Article  PubMed  Google Scholar 

  31. Verma C, Kaewkangsadan V, Eremin JM, Cowley GP, Ilyas M, El-Sheemy MA, Eremin O (2015) Natural killer (NK) cell profiles in blood and tumour in women with large and locally advanced breast cancer (LLABC) and their contribution to a pathological complete response (PCR) in the tumour following neoadjuvant chemotherapy (NAC): differential restoration of blood profiles by NAC and surgery. J Transl Med 13:180

    Article  PubMed  PubMed Central  Google Scholar 

  32. Toliopoulos IK, Simos YV, Daskalou TA, Verginadis II, Evangelou AM, Karkabounas SC (2011) Inhibition of platelet aggregation and immunomodulation of NK lymphocytes by administration of ascorbic acid. Indian J Exp Biol 49:904–908

    CAS  PubMed  Google Scholar 

  33. Contursi A, Sacco A, Grande R, Dovizio M, Patrignani P (2017) Platelets as crucial partners for tumor metastasis: from mechanistic aspects to pharmacological targeting. Cell Mol Life Sci. https://doi.org/10.1007/s00018-017-2536-7

    PubMed  Google Scholar 

  34. Floyd CN, Passascquale G, Ferro A (2012) Comparative pharmacokinetics and pharmacodynamics of platelet adenosine diphosphate receptor antagonists and their clinical implications. Clin Pharmacokinet 51:429–442

    Article  CAS  PubMed  Google Scholar 

  35. Lyngby JG, Court MH, Lee PM (2017) Validation of a method for quantitation of the clopidogrel active metabolite, clopidogrel, clopidogrel carboxylic acid, and 2-oxo-clopidogrel in feline plasma. J Vet Cardiol 19:384–395

    Article  PubMed  Google Scholar 

  36. Labelle M, Begum S, Hynes RO (2014) Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci 111:E3053–E3061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kirkby NS, Lundberg MH, Chan MV, Vojnovic I, Solomon AB, Emerson M, Mitchell JA, Warner TD (2013) Blockade of the purinergic P2Y12 receptor greatly increases the platelet inhibitory actions of nitric oxide. Proc Natl Acad Sci USA 110:15782–15787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Maseneni S, Donzelli M, Taegtmeyer AB et al (2012) Toxicity of clopidogrel and ticlopidine on human myeloid progenitor cells: importance of metabolites. Toxicology 299:139–145

    Article  CAS  PubMed  Google Scholar 

  39. Lonsdorf AS, Kreamer BF, Fahrleitner M et al (2012) Engagement of aIIbb3 (GPIIb/IIIa) with amb3 integrin mediates interaction of melanoma cells with platelets: a connection to hematogenous metastasis. J Biol Chem 287:2168–2178

    Article  CAS  PubMed  Google Scholar 

  40. Jackson W 3rd, Sosnoski DM, Ohanessian SE, Chandler P, Mobley A, Meisel KD, Mastro AM (2017) Role of megakaryocytes in breast cancer metastasis to bone. Cancer Res 77:1942–1954

    Article  CAS  PubMed  Google Scholar 

  41. Schumacher D, Strilic B, Sivaraj KK et al (2013) Platelet-derived nucleotides promote tumor-cell trans-endothelial migration and metastasis via P2Y2 receptor. Cancer Cell 24:130–137

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank Terry LeVatte for technical assistance. This research was funded by the Canadian Breast Cancer Foundation and the Dalhousie University Department of Surgery. C. Brien and A. Gareau were supported by a Cancer Research Training Program studentship and an Izaak Walton Killam Health Centre post-graduate fellowship, respectively.

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Authors and Affiliations

  1. Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada

    Alison J. Gareau, Simon Gebremeskel, Robert S. Liwski, Brent Johnston & Michael Bezuhly

  2. Izaak Walton Killam Health Centre, Halifax, NS, Canada

    Alison J. Gareau & Michael Bezuhly

  3. School of Medicine, University College Cork, Cork, Ireland

    Colin Brien

  4. Department of Pathology, Dalhousie University, Halifax, NS, Canada

    Robert S. Liwski & Brent Johnston

  5. Department of Pediatrics, Dalhousie University, Halifax, NS, Canada

    Brent Johnston

  6. Division of Plastic and Reconstructive Surgery, Department of Surgery, Dalhousie University, Halifax, NS, Canada

    Michael Bezuhly

  7. Department of Surgery, Dalhousie University, IWK Health Centre, 5850/5980 University Avenue, PO Box 9700, Halifax, NS, B3K 6R8, Canada

    Michael Bezuhly

Authors
  1. Alison J. Gareau
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  2. Colin Brien
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  3. Simon Gebremeskel
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  4. Robert S. Liwski
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  5. Brent Johnston
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  6. Michael Bezuhly
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Correspondence to Michael Bezuhly.

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Gareau, A.J., Brien, C., Gebremeskel, S. et al. Ticagrelor inhibits platelet–tumor cell interactions and metastasis in human and murine breast cancer. Clin Exp Metastasis 35, 25–35 (2018). https://doi.org/10.1007/s10585-018-9874-1

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  • DOI: https://doi.org/10.1007/s10585-018-9874-1

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