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Platelet-targeted pharmacologic treatments as anti-cancer therapy

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Abstract

Platelets act as multifunctional cells participating in immune response, inflammation, allergy, tissue regeneration, and lymphoangiogenesis. Among the best-established aspects of a role of platelets in non-hemostatic or thrombotic disorders, there is their participation in cancer invasion and metastasis. The interaction of many different cancer cells with platelets leads to platelet activation, and on the other hand platelet activation is strongly instrumental to the pro-carcinogenic and pro-metastatic activities of platelets. It is thus obvious that over the last years a lot of interest has focused on the possible chemopreventive effect of platelet-targeted pharmacologic treatments. This article gives an overview of the platelet-targeted pharmacologic approaches that have been attempted in the prevention of cancer development, progression, and metastasis, including the application of anti-platelet drugs currently used for cardiovascular disease and of new and novel pharmacologic strategies. Despite the fact that very promising results have been obtained with some of these approaches in pre-clinical models, with the exclusion of aspirin, clinical evidence of a beneficial effect of anti-platelet agents in cancer is however still largely missing. Future studies with platelet-targeted drugs in cancer must carefully deal with design issues, and in particular with the careful selection of patients, and/or explore novel platelet targets in order to provide a solution to the critical issue of the risk/benefit profile of long-term anti-platelet therapy in the prevention of cancer progression and dissemination.

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References

  1. Simmons, D. L., Botting, R. M., & Hla, T. (2004). Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacological Reviews, 56(3), 387–437.

    Article  CAS  PubMed  Google Scholar 

  2. Iniguez, M. A., Cacheiro-Llaguno, C., Cuesta, N., Diaz-Munoz, M. D., & Fresno, M. (2008). Prostanoid function and cardiovascular disease. Archives of Physiology and Biochemistry, 114(3), 201–209.

    Article  CAS  PubMed  Google Scholar 

  3. Gresele, P., Deckmyn, H., Nenci, G. G., & Vermylen, J. (1991). Thromboxane synthase inhibitors, thromboxane receptor antagonists and dual blockers in thrombotic disorders. Trends in Pharmacological Sciences, 12(4), 158–163.

    Article  CAS  PubMed  Google Scholar 

  4. Nakahata, N. (2008). Thromboxane A2: physiology/pathophysiology, cellular signal transduction and pharmacology. Pharmacological Therapy, 118(1), 18–35.

    Article  CAS  Google Scholar 

  5. Vane, J. R. (1972). Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature: New Biology, 231(25), 232–235.

    Google Scholar 

  6. Roth, G. J., Stanford, N., & Majerus, P. W. (1975). Acetylation of prostaglandin synthase by aspirin. Proceedings of the National Academy of Sciences USA, 72(8), 3073–3076.

    Article  CAS  Google Scholar 

  7. Gasic, G. J., Gasic, T. B., & Murphy, S. (1972). Anti-metastatic effect of aspirin. Lancet, 2(7783), 932–933.

    Article  CAS  PubMed  Google Scholar 

  8. Gasic, G. J., Gasic, T. B., & Stewart, C. C. (1968). Anti-metastatic effect associated with platelet reduction. Proceeding of the National Academy of Science USA, 61(1), 46–52.

    Article  CAS  Google Scholar 

  9. Jaffe, B. M. (1974). Prostaglandin and cancer: an update. Prostaglandins, 6(6), 453–461.

    Article  CAS  PubMed  Google Scholar 

  10. Bennett, A., & Del Tacca, M. (1975). Proceedings: prostaglandins in human colonic carcinoma. Gut, 16(5), 409.

    CAS  PubMed  Google Scholar 

  11. Reddy, B. S., Rao, C. V., Rivenson, A., & Kelloff, G. (1993). Inhibitory effect of aspirin on azoxymethane-induced colon carcinogenesis in F344 rats. Carcinogenesis, 14(8), 1493–1497.

    Article  CAS  PubMed  Google Scholar 

  12. Duperron, C., & Castonguay, A. (1997). Chemopreventive efficacies of aspirin and sulindac against lung tumorigenesis in A/J mice. Carcinogenesis, 18(5), 1001–1006.

    Article  CAS  PubMed  Google Scholar 

  13. Tian, Y., Ye, Y., Gao, W., et al. (2011). Aspirin promotes apoptosis in a murine model of colorectal cancer by mechanisms involving downregulation of IL-6-STAT3 signaling pathway. International Journal of Colorectal Disease, 26(1), 13–22.

    Article  PubMed  Google Scholar 

  14. Vad, N. M., Kudugunti, S. K., Wang, H., Bhat, G. J., & Moridani, M. Y. (2014). Efficacy of acetylsalicylic acid (aspirin) in skin B16-F0 melanoma tumor-bearing C57BL/6 mice. Tumour Biology, 35(5), 4967–4976.

    Article  CAS  PubMed  Google Scholar 

  15. Cathomas, G. (2014). PIK3CA in colorectal cancer. Frontiers in Oncology, 4, 1–4.

    Article  Google Scholar 

  16. Okumura, H., Uchikado, Y., Setoyama, T., et al. (2014). Biomarkers for predicting the response of esophageal squamous cell carcinoma to neoadjuvant chemoradiation therapy. Surgery Today, 44(3), 421–428.

    Article  CAS  PubMed  Google Scholar 

  17. Reimers, M. S., Bastiaannet, E., Langley, R. E., et al. (2014). Expression of HLA class I antigen, aspirin use, and survival after a diagnosis of colon cancer. JAMA International Medicine, 174(5), 732–739.

    Article  CAS  Google Scholar 

  18. Henrich, K. O., Bauer, T., Schulte, J., et al. (2011). CAMTA1, a 1p36 tumor suppressor candidate, inhibits growth and activates differentiation programs in neuroblastoma cells. Cancer Research, 71(8), 3142–3151.

    Article  CAS  PubMed  Google Scholar 

  19. Mikami, J., Kurokawa, Y., Takahashi, T., et al. (2016). Antitumor effect of antiplatelet agents in gastric cancer cells: an in vivo and in vitro study. Gastric Cancer, 19(3), 817–826.

    Article  CAS  PubMed  Google Scholar 

  20. Guillem-Llobat, P., Dovizio, M., Bruno, A., et al. (2016). Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells. Oncotarget, 7(22), 32462–32477.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Uluçkan, O., Eagleton, M. C., Floyd, D. H., et al. (2008). APT102, a novel adpase, cooperates with aspirin to disrupt bone metastasis in mice. Journal of Cellular Biochemistry, 104(4), 1311–1323.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kune, G. A., Kune, S., & Watson, L. F. (1988). Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study. Cancer Research, 48(15), 4399–4404.

    CAS  PubMed  Google Scholar 

  23. Algra, A. M., & Rothwell, P. M. (2012). Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncology, 13(5), 518–527.

    Article  CAS  PubMed  Google Scholar 

  24. Baron, J. A., Cole, B. F., & Sandler, R. S. (2003). A randomized trial of aspirin to prevent colorectal adenomas. New England Journal of Medicine, 348(10), 891–899.

    Article  CAS  PubMed  Google Scholar 

  25. Sandler, R. S., Halabi, S., & Baron, J. A. (2003). A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. New England Journal of Medicine, 348(10), 883–890.

    Article  CAS  PubMed  Google Scholar 

  26. Logan, R.F., Grainge, M.J., & Shepherd, V.C., et al.; (2008) ukCAP Trial Group. Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology, 134(1), 29–38.

  27. Benamouzig, R., Deyra, J., Martin, A., et al. (2003). Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial. Gastroenterology, 125(2), 328–336.

    Article  CAS  PubMed  Google Scholar 

  28. Cole, B. F., Logan, R. F., Halabi, S., et al. (2009). Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. Journal of the National Cancer Institute, 101(4), 256–266.

    Article  CAS  PubMed  Google Scholar 

  29. Burn, J., Bishop, D. T., Mecklin, J. P., & CAPP2 Investigators. (2008). Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. New England Journal of Medicine, 359(24), 2567–2578.

    Article  CAS  PubMed  Google Scholar 

  30. Cooke, N. M., Spillane, C. D., 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  CAS  Google Scholar 

  31. Antithrombotic Trialists’ Collaboration. (2002). Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. British Medical Journal, 324(7329), 71–86.

    Article  Google Scholar 

  32. Gresele, P. (2013). Antiplatelet agents in clinical practice and their haemorrhagic risk. Blood Transfusion, 11(3), 349–356.

    PubMed  PubMed Central  Google Scholar 

  33. Stürmer, T., Glynn, R. J., Lee, I. M., Manson, J. E., Buring, J. E., & Hennekens, C. H. (1998). Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians’ Health Study. Annals of Internal Medicine, 128(9), 713–720.

    Article  PubMed  Google Scholar 

  34. Rothwell, P. M., Wilson, M., & Elwin, C. E. (2010). Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet, 376(9754), 1741–1750.

    Article  CAS  PubMed  Google Scholar 

  35. Rothwell, P. M., Fowkes, F. G., Belch, J. F., Ogawa, H., Warlow, C. P., & Meade, T. W. (2011). Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet, 377(9759), 31–41.

    Article  CAS  PubMed  Google Scholar 

  36. Rothwell, P. M., Wilson, M., Price, J. F., Belch, J. F., Meade, T. W., & Mehta, Z. (2012). Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet, 379(9826), 1591–1601.

    Article  CAS  PubMed  Google Scholar 

  37. Rothwell, P. M., Price, J. F., Fowkes, F. G., et al. (2012). Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet, 379(9826), 1602–1612.

    Article  CAS  PubMed  Google Scholar 

  38. Thun, M. J., Jacobs, E. J., & Patrono, C. (2012). The role of aspirin in cancer prevention. Nature Reviews Clinical Oncology, 9(5), 259–267.

    Article  CAS  PubMed  Google Scholar 

  39. Chubak, J., Whitlock, E. P., Williams, S. B., et al. (2016). Aspirin for the prevention of cancer incidence and mortality: systematic evidence reviews for the U.S. Preventive Services Task Force. Annals of Internal Medicine, 164(12), 814–825.

    Article  PubMed  Google Scholar 

  40. Gresele, P., Momi, S., & Falcinelli, E. (2011). Anti-platelet therapy: phosphodiesterase inhibitors. British Journal of Clinical Pharmacology, 72(4), 634–646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Faxon, D.P., Creager, M.A., Smith, S.C., et al., (2004) American Heart Association. Atherosclerotic vascular disease conference: executive summary: atherosclerotic vascular disease conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation, 109(21), 2595–2604.

  42. Murata, K., Kameyama, M., Fukui, F., et al. (1999). Phosphodiesterase type III inhibitor, cilostazol, inhibits colon cancer cell motility. Clinical and Experimental Metastasis, 17(6), 525–530.

    Article  CAS  PubMed  Google Scholar 

  43. Uzawa, K., Kasamatsu, A., Baba, T., et al. (2013). Targeting phosphodiesterase 3B enhances cisplatin sensitivity in human cancer cells. Cancer Medicine, 2(1), 40–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Okoshi, H., Hakomori, S., Nisar, M., et al. (1991). Cell membrane signaling as target in cancer therapy II: inhibitory effect of N,N,N-trimethylsphingosine on metastatic potential of murine B16 melanoma cell line through blocking of tumor cell-dependent platelet aggregation. Cancer Research, 51(22), 6019–6025.

    CAS  PubMed  Google Scholar 

  45. Inufusa, H., Adachi, T., Nakamura, M., Shindo, K., Yasutomi, M., & Kimura, Y. (1995). Inhibition of experimental metastasis of human adenocarcinoma by cilostazol, a platelet phosphodiesterase inhibitor. Oncology Report, 2(6), 1079–1083.

    CAS  Google Scholar 

  46. Akcan, A., Kucuk, C., Ok, E., Canoz, O., Muhtaroglu, S., et al. (2006). The effect of amrinone on liver regeneration in experimental hepatic resection model. The Journal of Surgical Research, 130(1), 66–72.

    Article  CAS  PubMed  Google Scholar 

  47. Savai, R., Pullamsetti, S. S., Banat, G. A., et al. (2010). Targeting cancer with phosphodiesterase inhibitors. Expert Opinion on Investigational Drugs, 19(1), 117–131.

    Article  CAS  PubMed  Google Scholar 

  48. Strowitzki, M. J., Dold, S., von Heesen, M., et al. (2014). The phosphodiesterase 3 inhibitor cilostazol does not stimulate growth of colorectal liver metastases after major hepatectomy. Clinical and Experimental Metastasis, 31(7), 795–803.

    Article  CAS  PubMed  Google Scholar 

  49. Gresele, P., Zoja, C., Deckmyn, H., Arnout, J., Vermylen, J., & Verstraete, M. (1983). Dipyridamole inhibits platelet aggregation in whole blood. Thrombosis and Haemostasis, 50(4), 852–856.

    CAS  PubMed  Google Scholar 

  50. Gresele, P., Arnout, J., Deckmyn, H., & Vermylen, J. (1986). Mechanism of the antiplatelet action of dipyridamole in whole blood: modulation of adenosine concentration and activity. Thrombosis and Haemostasis, 55(1), 12–18.

    CAS  PubMed  Google Scholar 

  51. Gresele, P., Arnout, J., & Vermylen, J. (1987). Dipyridamole inhibits leukotriene B4 synthesis. Thrombosis and Haemostasis, 57(2), 235.

    CAS  PubMed  Google Scholar 

  52. Deckmyn, H., Gresele, P., Arnout, J., Todisco, A., & Vermylen, J. (1984). Prolonging prostacyclin production by nafazatrom or dipyridamole. Lancet, 2(8399), 410–411.

    Article  CAS  PubMed  Google Scholar 

  53. Tzanakakis, G. N., Agarwal, K. C., & Vezeridis, M. P. (1993). Prevention of human pancreatic cancer cell-induced hepatic metastasis in nude mice by dipyridamole and its analog RA-233. Cancer, 71(8), 2466–2471.

    Article  CAS  PubMed  Google Scholar 

  54. Desai, P. B., Duan, J., Sridhar, R., & Damle, B. D. (1997). Reversal of doxorubicin resistance in multidrug resistant melanoma cells in vitro and in vivo by dipyridamole. Methods and Findings in Experimental Clinical Pharmacology, 19(4), 231–239.

    CAS  Google Scholar 

  55. Spano, D., Marshall, J. C., Marino, N., et al. (2013). Dipyridamole prevents triple-negative breast-cancer progression. Clinical and Experimental Metastasis, 30(1), 47–68.

    Article  CAS  PubMed  Google Scholar 

  56. Goda, A. E., Yoshida, T., Horinaka, M., et al. (2008). Mechanisms of enhancement of TRAIL tumoricidal activity against human cancer cells of different origin by dipyridamole. Oncogene, 27(24), 3435–3445.

    Article  CAS  PubMed  Google Scholar 

  57. Shalinsky, D. R., Andreeff, M., & Howell, S. B. (1990). Modulation of drug sensitivity by dipyridamole in multidrug resistant tumor cells in vitro. Cancer Research, 50(23), 7537–7543.

    CAS  PubMed  Google Scholar 

  58. Rhodes, E. L., Misch, K. J., Edwards, J. M., & Jarrett, P. E. (1985). Dipyridamole for treatment of melanoma. Lancet, 1(8430), 693.

    Article  CAS  PubMed  Google Scholar 

  59. Kohnoe, S., Maehara, Y., Takahashi, I., Emi, Y., Baba, H., & Sugimachi, K. (1998). Treatment of advanced gastric cancer with 5-fluorouracil and cisplatin in combination with dipyridamole. International Journal of Oncology, 13(6), 1203–1206.

    CAS  PubMed  Google Scholar 

  60. Todd, K. E., Gloor, B., Lane, J. S., Isacoff, W. H., & Reber, H. A. (1998). Resection of locally advanced pancreatic cancer after downstaging with continuous-infusion 5-fluorouracil, mitomycin-C, leucovorin, and dipyridamole. Journal of Gastrointestinal Surgery, 2(2), 159–166.

    Article  CAS  PubMed  Google Scholar 

  61. Isacoff, W. H., Bendetti, J. K., Barstis, J. J., Jazieh, A. R., Macdonald, J. S., & Philip, P. A. (2007). Phase II trial of infusional fluorouracil, leucovorin, mitomycin, and dipyridamole in locally advanced unresectable pancreatic adenocarcinoma: SWOG S9700. Journal of Clinical Oncology, 25(13), 1665–1669.

    Article  CAS  PubMed  Google Scholar 

  62. Cusack, N. J., & Hourani, S. M. O. (2000). Platelet P2 receptors: from curiosity to clinical targets. Journal of Autonomous Nervous System, 81(1–3), 37–43.

    Article  CAS  Google Scholar 

  63. Burnstock, G. (1972). Purinergic nerves. Pharmacological Reviews, 24(3), 509–581.

    CAS  PubMed  Google Scholar 

  64. Hollopeter, G., Jantzen, H. M., Vincent, D., et al. (2001). Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature, 409(6817), 202–207.

    Article  CAS  PubMed  Google Scholar 

  65. Andre, P., Delaney, S. M., La Rocca, T., et al. (2003). P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries. Journal of Clinical Investigation, 112(3), 398–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dangelmaier, C., Jin, J., Smith, J. B., & Kunapuli, S. P. (2001). Potentiation of thromboxane A2-induced platelet secretion by Gi signaling through the phosphoinositide-3 kinase pathway. Thrombosis and Haemostasis, 85(2), 341–348.

    CAS  PubMed  Google Scholar 

  67. Dorsam, R. T., Kim, S., Jin, J., & Kunapuli, S. P. (2002). Coordinated signaling through both G12/13 and G(i) pathways is sufficient to activate GPIIb/IIIa in human platelets. Journal of Biological Chemistry, 277(49), 47588–47595.

    Article  CAS  PubMed  Google Scholar 

  68. Dorsam, R. T., & Kunapuli, S. P. (2004). Central role of the P2Y12 receptor in platelet activation. Journal of Clinical Investigation, 113(3), 340–345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. van Gestel, M. A., Heemskerk, J. W., Slaaf, D. W., et al. (2003). In vivo blockade of platelet ADP receptor P2Y12 reduces embolus and thrombus formation but not thrombus stability. Arteriosclerosis Thrombosis and Vascular Biology, 23(3), 518–523.

    Article  Google Scholar 

  70. Woulfe, D., Jiang, H., Mortensen, R., Yang, J., & Brass, L. F. (2002). Activation of Rap1B by G(i) family members in platelets. Journal of Biological Chemistry, 277(26), 23382–23390.

    Article  CAS  PubMed  Google Scholar 

  71. Gachet, C. (2012). P2Y12 receptors in platelets and other hematopoietic and non-hematopoietic cells. Purinergic Signal, 8(3), 609–619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Di Virgilio, F. (2012). Purines, purinergic receptors, and cancer. Cancer Research, 72(21), 5441–5447.

    Article  PubMed  CAS  Google Scholar 

  73. Aymeric, L., Apetoh, L., Ghiringhelli, F., et al. (2010). Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity. Cancer Research, 70(3), 855–858.

    Article  CAS  PubMed  Google Scholar 

  74. Boukerche, H., Berthier-Vergnes, O., Penin, F., et al. (1994). Human melanoma cell lines differ in their capacity to release ADP and aggregate platelets. British Journal of Haematology, 87(4), 763–772.

    Article  CAS  PubMed  Google Scholar 

  75. Ordinas, A., Díaz-Ricart, M., Almirall, L., & Bastida, E. (1990). The role of platelets in cancer metastasis. Blood Coagulation and Fibrinolysis, 1(6), 707–711.

    CAS  PubMed  Google Scholar 

  76. Wang, Y., Sun, Y., Li, D., et al. (2013). Platelet P2Y12 is involved in murine pulmonary metastasis. PloS One, 8(11), e80780.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Coupland, L. A., & Parish, C. R. (2014). Platelets, selectins, and the control of tumor metastasis. Seminars in Oncology, 41(3), 422–434.

    Article  CAS  PubMed  Google Scholar 

  78. Johansson, J., Tabor, V., Wikell, A., Jalkanen, S., & Fuxe, J. (2015). TGF-β1-induced epithelial-mesenchymal transition promotes monocyte/macrophage properties in breast cancer cells. Frontiers in Oncology, 5, 3.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Contractor, H., & Ruparelia, N. (2012). Advances in antiplatelet therapy for acute coronary syndromes. Postgraduate Medical Journal, 88(1041), 391–396.

    Article  CAS  PubMed  Google Scholar 

  80. Collet, J. P., Hulot, J. S., Pena, A., et al. (2009). Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet, 373(9660), 309–317.

    Article  CAS  PubMed  Google Scholar 

  81. Herbert, J. M., & Savi, P. (2003). P2Y12, a new platelet ADP receptor, target of clopidogrel. Seminars in Vascular Medicine, 3(2), 113–122.

    Article  PubMed  Google Scholar 

  82. Kazui, M., Nishiya, Y., Ishizuka, T., et al. (2010). Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metabolism and Disposition, 38(1), 92–99.

    Article  CAS  PubMed  Google Scholar 

  83. Pereillo, J. M., Maftouh, M., Andrieu, A., et al. (2002). Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metabolism and Disposition, 30(11), 1288–1295.

    Article  CAS  PubMed  Google Scholar 

  84. Bambace, N. M., Levis, J. E., & Holmes, C. E. (2010). The effect of P2Y-mediated platelet activation on the release of VEGF and endostatin from platelets. Platelets, 21(2), 85–93.

    Article  CAS  PubMed  Google Scholar 

  85. Klein-Soyer, C., Céraline, J., Orvain, C., de la Salle, C., Bergerat, J. P., & Cazenave, J. P. (1997). Angiogenesis inhibitor SR 25989 upregulates thrombospondin-1 expression in human vascular endothelial cells and foreskin fibroblasts. Biology of the Cell, 89(4), 295–307.

    Article  CAS  PubMed  Google Scholar 

  86. Ma, H., Hara, A., Xiao, C. Y., et al. (2001). Increased bleeding tendency and decreased susceptibility to thromboembolism in mice lacking the prostaglandin E2 receptor subtype EP3. Circulation, 104(10), 1176–1180.

    Article  CAS  PubMed  Google Scholar 

  87. Sitia, G., Aiolfi, R., Di Lucia, P., et al. (2012). Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proceeding of the National Academy of Sciences U S A, 109(32), E2165–E2172.

    Article  CAS  Google Scholar 

  88. Pandey, A., Sarangi, S., Chien, K., et al. (2014). Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery. Nanotechnology, 25(44), 445101.

    Article  PubMed  CAS  Google Scholar 

  89. Roop, R. P., Naughton, M. J., Van Poznak, C., et al. (2013). A randomized phase II trial investigating the effect of platelet function inhibition on circulating tumor cells in patients with metastatic breast cancer. Clinical Breast Cancer, 13(6), 409–415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Choe, K. S., Correa, D., Jani, A. B., & Liauw, S. L. (2010). The use of anticoagulants improves biochemical control of localized prostate cancer treated with radiotherapy. Cancer, 116(7), 1820–1826.

    Article  CAS  PubMed  Google Scholar 

  91. Hicks, B. M., Murray, L. J., Hughes, C., & Cardwell, C. R. (2015). Clopidogrel use and cancer-specific mortality: a population-based cohort study of colorectal, breast and prostate cancer patients. Pharmacoepidemiological Drug Safety, 24(8), 830–840.

    Article  CAS  Google Scholar 

  92. Husted, S., Emanuelsson, H., Heptinstall, S., et al. (2006). Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. European Heart Journal, 27(9), 1038–1047.

    Article  CAS  PubMed  Google Scholar 

  93. Teng, R., Oliver, S., Hayes, M. A., & Butler, K. (2010). Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metabolism and Disposable, 38(9), 1514–1521.

    Article  CAS  Google Scholar 

  94. Gebremeskel, S., LeVatte, T., Liwski, R. S., Johnston, B., & Bezuhly, M. (2015). The reversible P2Y12 inhibitor ticagrelor inhibits metastasis and improves survival in mouse models of cancer. International Journal of Cancer, 136(1), 234–240.

    Article  CAS  PubMed  Google Scholar 

  95. Bonaca, M. P., Bhatt, D. L., Cohen, M. P. H., et al. (2015). Long-term use of ticagrelor in patients with prior myocardial infarction. New England Journal of Medicine, 372(19), 1791–1800.

    Article  PubMed  Google Scholar 

  96. Serebruany, V. L., Cherepanov, V., Cabrera-Fuentes, H. A., & Kim, M. H. (2015). Solid cancers after antiplatelet therapy: confirmations, controversies, and challenges. Thrombosis and Haemostasis, 114(6), 1104–1112.

    Article  PubMed  Google Scholar 

  97. Serebruany, V. L., Dinicolantonio, J. J., Can, M. M., Pershukov, I. V., & Kuliczkowski, W. (2013). Gastrointestinal adverse events after dual antiplatelet therapy: clopidogrel is safer than ticagrelor, but prasugrel data are lacking or inconclusive. Cardiology, 126(1), 35–40.

    Article  CAS  PubMed  Google Scholar 

  98. Unger, E. F. (2009). Weighing benefits and risks—the FDA’s review of prasugrel. New England Journal of Medicine, 361(10), 942–945.

    Article  CAS  PubMed  Google Scholar 

  99. Floyd, J. S., & Serebruany, V. L. (2010). Prasugrel as a potential cancer promoter: review of the unpublished data. Archives of Internal Medicine, 170(12), 1078–1080.

    Article  CAS  PubMed  Google Scholar 

  100. Roe, M.T., Cyr, D.D., Eckart, D., et al.; (2016) TRILOGY ACS Investigators. Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs clopidogrel following acute coronary syndrome. European Heart Journal, 37(4), 412–422.

  101. Mauri, L., Kereiakes, D.J., Yeh, R.W., et al. (2014). DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. New England Journal of Medicine, 371(23), 2155–2166.

  102. Kotronias, R. A., Kwok, C. S., Wong, C. W., Kinnaird, T., Zaman, A., & Mamas, M. A. (2017). Cancer event rate and mortality with thienopyridines: a systematic review and meta-analysis. Drug Safety, 40(3), 229–240.

    Article  CAS  PubMed  Google Scholar 

  103. Leader, A., Zelikson-Saporta, R., Pereg, D., et al. (2017). The effect of combined aspirin and clopidogrel treatment on cancer incidence. The American Journal of Medicine. doi:10.1016/j.amjmed.2017.01.022.

  104. Shattil, S. J., Kashiwagi, H., & Pampori, N. (1998). Integrin signaling: the platelet paradigm. Blood, 91(8), 2645–2657.

    CAS  PubMed  Google Scholar 

  105. Schrör, K., & Weber, A. (2003). Comparative pharmacology of GP IIb/IIIa antagonists. Journal of Thrombosis and Thrombolysis, 15(5), 71–80.

    Article  PubMed  Google Scholar 

  106. Salame, M., Verheye, S., More, R., King 3rd, S. B., & Chronos, N. (1999). GPIIbIIIa inhibitors as adjunctive therapy in acute myocardial infarction. International Journal of Cardiology, 69(3), 231–236.

    Article  CAS  PubMed  Google Scholar 

  107. Ahrens, I., Bode, C., & Zirlik, A. (2014). Anticoagulation during and after acute coronary syndrome. Hämostaseologie, 34(1), 72–77.

    Article  CAS  PubMed  Google Scholar 

  108. Clezardin, P., Drouin, J., Morel-Kopp, M. C., et al. (1993). Role of platelet membrane glycoproteins Ib/IX and IIb/IIIa, and of platelet alpha-granule proteins in platelet aggregation induced by human osteosarcoma cells. Cancer Research, 53(19), 4695–4700.

    CAS  PubMed  Google Scholar 

  109. Santos-Martinez, M. J., Medina, C., Jurasz, P., & Radomski, M. W. (2008). Role of metalloproteinases in platelet function. Thrombosis Research, 121(4), 535–542.

    Article  CAS  PubMed  Google Scholar 

  110. Bakewell, S. J., Nestor, P., Prasad, S., et al. (2003). Platelet and osteoclast beta3 integrins are critical for bone metastasis. Proceedings of the National Academy of Science U S A, 100(24), 14205–14210.

    Article  CAS  Google Scholar 

  111. Liu, Z., Wang, F., & Chen, X. (2008). Integrin alpha(v)beta(3)-targeted cancer therapy. Drug Development Research, 69(6), 329–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Bennett, J. S., Chan, C., Vilaire, G., Mousa, S. A., & DeGrado, W. F. (1997). Agonist-activated alphavbeta3 on platelets and lymphocytes binds to the matrix protein osteopontin. Journal of Biological Chemistry, 272(13), 8137–8140.

    Article  CAS  PubMed  Google Scholar 

  113. Wilder, R. L. (2002). Integrin alpha V beta 3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases. Annals of Rheumatisms Disease, 61(Suppl 2), 96–99.

    Article  Google Scholar 

  114. Brooks, P. C., Clark, R. A., & Cheresh, D. A. (1994). Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science, 264(5158), 569–571.

    Article  CAS  PubMed  Google Scholar 

  115. Kumar, C. C. (2003). Integrin alpha v beta 3 as a therapeutic target for blocking tumor-induced angiogenesis. Current Drug Targets, 4(2), 123–131.

    Article  CAS  PubMed  Google Scholar 

  116. Weber, M. R., Zuka, M., Lorger, M., et al. (2016). Activated tumor cell integrin αvβ3 cooperates with platelets to promote extravasation and metastasis from the blood stream. Thrombosis Research, 140(Suppl 1), S27–S36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tesfamariam, B. (2016). Involvement of platelets in tumor cell metastasis. Pharmacological. Therapy, 157, 112–119.

    Article  CAS  Google Scholar 

  118. Lonsdorf, A. S., Kramer, B. F., Fahrleitner, M., et al. (2012). Engagement of alpha(IIb)beta(3) (GPIIb/IIIa) with alphanubeta3 integrin mediates interaction of melanoma cells with platelets: a connection to hematogenous metastasis. Journal of Biological Chemistry, 287(3), 2168–2178.

    Article  CAS  PubMed  Google Scholar 

  119. Gomes, N., Vassy, J., Lebos, C., Arbeille, B., Legrand, C., & Fauvel-Lafeve, F. (2004). Breast adenocarcinoma cell adhesion to the vascular subendothelium in whole blood and under flow conditions: effects of alphavbeta3 and alphaIIbbeta3 antagonists. Clinical and Experimental Metastasis, 21(6), 553–561.

    Article  CAS  PubMed  Google Scholar 

  120. Harris, T. D., Kalogeropoulos, S., Nguyen, T., et al. (2003). Design, synthesis, and evaluation of radiolabeled integrin alpha v beta 3 receptor antagonists for tumor imaging and radiotherapy. Cancer Biotherapy and Radiopharmaceuticals, 18(4), 627–641.

    Article  CAS  PubMed  Google Scholar 

  121. Amirkhosravi, A., Mousa, S. A., Amaya, M., et al. (2003). Inhibition of tumor cell-induced platelet aggregation and lung metastasis by the oral GpIIb/IIIa antagonist XV454. Thrombosis and Haemostasis, 90(3), 549–554.

    CAS  PubMed  Google Scholar 

  122. Sheu, J. R., Lin, C. H., Chung, J.l., Teng, C. M., & Huang, T. F. (1992). Triflavin, an Arg-Gly-Asp containing snake venom peptide, inhibits aggregation of human platelets induced by human hepatoma cell line. Thrombosis Research, 66(6), 679–691.

  123. Chiang, H. S., Swaim, M. W., & Huang, T. F. (1994). Characterization of platelet aggregation induced by human colon adenocarcinoma cells and its inhibition by snake venom peptides, trigramin and rhodostomin. British Journal of Haematology, 87(2), 325–331.

    Article  CAS  PubMed  Google Scholar 

  124. Borsig, L., Wong, R., Feramisco, J., Nadeau, D. R., Varki, N. M., & Varki, A. (2001). Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proceedings of the National Academy of Science U S A, 98(6), 3352–3357.

    Article  CAS  Google Scholar 

  125. Sobel, M., Fish, W. R., Toma, N., et al. (2001). Heparin modulates integrin function in human platelets. Journal of Vascular Surgery, 33(3), 587–594.

    Article  CAS  PubMed  Google Scholar 

  126. Zhang, C., Liu, Y., Gao, Y., et al. (2009). Modified heparins inhibit integrin alpha(IIb)beta(3) mediated adhesion of melanoma cells to platelets in vitro and in vivo. International Journal of Cancer, 125(9), 2058–2065.

    Article  CAS  PubMed  Google Scholar 

  127. Gutheil, J. C., Campbell, T. N., Pierce, P. R., et al. (2000). Targeted antiangiogenic therapy for cancer using vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. Clinical and Cancer Research, 6(8), 3056–3061.

    CAS  Google Scholar 

  128. Patel, S., Jenkins, J., Papadopolous, N., et al. (2001). Pilot study of vitaxin—an angiogenesis inhibitor—in patients with advanced leiomyosarcomas. Cancer, 92(5), 1347–1348.

    Article  CAS  PubMed  Google Scholar 

  129. Posey, J., Khazaeli, M., Del Grosso, A., et al. (2001). A pilot trial of vitaxin, a humanized anti-vitronectin receptor (anti-αvβ3) antibody in patients with metastatic cancer. Cancer Biotherapy and Radiopharmaceuticals, 16(2), 125–132.

    Article  CAS  PubMed  Google Scholar 

  130. Cai, W., Wu, Y., Chen, K., Cao, Q., Tice, D., & Chen, X. (2006). In vitro and in vivo characterization of 64Cu-labeled Abegrin, a humanized monoclonal antibody against integrin αvβ3. Cancer Research, 66(19), 9673–9681.

    Article  CAS  PubMed  Google Scholar 

  131. Hersey, P., Sosman, J., O'Day, S., et al. (2010). A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin αvβ3, +/− dacarbazine in patients with stage IV metastatic melanoma. Cancer, 116(6), 1526–1534.

    Article  CAS  PubMed  Google Scholar 

  132. Delbaldo, C., Raymond, E., Vera, K., et al. (2008). Phase I and pharmacokinetic study of etaracizumab (Abegrin), a humanized monoclonal antibody against αvβ3 integrin receptor, in patients with advanced solid tumors. Investigational New Drugs, 26(1), 35–43.

    Article  CAS  PubMed  Google Scholar 

  133. Dyke, C. M. (1999). Safety of glycoprotein IIb-IIIa inhibitors: a heart surgeon’s perspective. American Heart Journal, 138(4 pt 2), 307–316.

    Article  CAS  PubMed  Google Scholar 

  134. Gulba, D. C., Huber, K., Moll, S., & Dietz, R. (1998). Platelet inhibition: new agents, new strategies, new trials. Fibrinolysis and Proteolysis, 12(Suppl2), 13–23.

  135. Tam, S., Sassoli, P., Jordan, R., & Nakada, M. (1998). Abciximab (ReoPro, chimeric 7E3 Fab) demonstrates equivalent affinity and functional blockade of lycoprotein IIb/IIIa αvβ3 integrins. Circulation, 98(11), 1085–1091.

    Article  CAS  PubMed  Google Scholar 

  136. Antoniucci, D. (2007). Differences among GP IIb/IIIa inhibitors: different clinical benefits in non-ST-segment elevation acute coronary syndrome percutaneous coronary intervention patients. European Heart Journal, 9, A32–A36.

    Article  CAS  Google Scholar 

  137. Casserly, I., & Topol, E. (2002). Glycoprotein IIb/IIIa-antagonists—from bench to practice. Cellular and Molecular Life Sciences, 59(3), 478–500.

    Article  CAS  PubMed  Google Scholar 

  138. Amirkhosravi, A., Amaya, M., Siddiqui, F., Biggerstaff, J. P., Meyer, T. V., & Francis, J. L. (1999). Blockade of GPIIb/IIIa inhibits the release of vascular endothelial growth factor (VEGF) from tumor cell-activated platelets and experimental metastasis. Platelets, 10(5), 285–292.

    Article  CAS  PubMed  Google Scholar 

  139. Trikha, M., Zhou, Z., Timar, J., et al. (2002). Multiple roles for platelet GPIIb/IIIa and alphavbeta3 integrins in tumor growth, angiogenesis, and metastasis. Cancer Research, 62(10), 2824–2833.

    CAS  PubMed  Google Scholar 

  140. Tcheng, J. (2000). Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy: bleeding, reversal, thrombocytopenia, and retreatment. American Heart Journal, 139(2 pt 2), S38–S45.

    Article  CAS  PubMed  Google Scholar 

  141. Kononczuk, J., Surazynski, A., Czyzewska, U., et al. (2015). αIIbβ3-integrin ligands: abciximab and eptifibatide as proapoptotic factors in MCF-7 human breast cancer cells. Current Drug Targets, 16(13), 1429–1437.

    Article  CAS  PubMed  Google Scholar 

  142. Karlheinz, P. (2005). Antiplatelet drugs. In M. S. Runge (Ed.), Principles of molecular cardiology (Vol. 105, pp. 203–218). Totowa: Human Press.

    Google Scholar 

  143. Peter, K. (2005). Principles of molecular cardiology. Totowa: Humana Press.

    Google Scholar 

  144. Davì, G., Santilli, F., & Vazzana, N. (2012). Thromboxane receptors antagonists and/or synthase inhibitors. Handbook of Experimental Pharmacology, 210, 261–286.

    Article  CAS  Google Scholar 

  145. Honn, K. V. (1983). Inhibition of tumor cell metastasis by modulation of the vascular prostacyclin/thromboxane A2 system. Clinical and Experimental Metastasis, 1(2), 103–114.

    Article  CAS  PubMed  Google Scholar 

  146. Ogletree, M. L. (1987). Overview of physiological and pathophysiological effects of thromboxane A2. Federation Proceedings, 46(1), 133–138.

    CAS  PubMed  Google Scholar 

  147. Nie, D., Lamberti, M., Zacharek, A., et al. (2000). Thromboxane A2 regulation of endothelial cell migration, angiogenesis, and tumor metastasis. Biochemical and Biophysical Research Communication, 267, 245–251.

    Article  CAS  Google Scholar 

  148. de Leval, X., Benoit, V., Delarge, J., et al. (2003). Pharmacological evaluation of the novel thromboxane modulator BM-567 (II/II). Effects of BM-567 on osteogenic sarcoma-cell-induced platelet aggregation. Prostaglandins and Leukotriene Essential Fatty Acids, 68(1), 55–59.

    Article  Google Scholar 

  149. Mehta, P., Lawson, D., Ward, M. B., Lee-Ambrose, L., & Kimura, A. (1986). Effects of thromboxane A2 inhibition on osteogenic sarcoma cell-induced platelet aggregation. Cancer Research, 46(10), 5061–5063.

    CAS  PubMed  Google Scholar 

  150. Yokoyama, I., Hayashi, S., Kobayashi, T., et al. (1995). Prevention of experimental hepatic metastasis with thromboxane synthase inhibitor. Research and Experimental Medicine, 195(4), 209–215.

    Article  CAS  Google Scholar 

  151. Vezza, R., Roberti, R., Nenci, G. G., & Gresele, P. (1993). Prostaglandin E2 potentiates platelet aggregation by priming protein kinase C. Blood, 82(9), 2704–2713.

    CAS  PubMed  Google Scholar 

  152. Fabre, J. E., Nguyen, M. T., Athirakul, K., et al. (2001). Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation. Journal of Clinical Investigation, 107(5), 603–610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Gross, S., Tilly, P., Hentsch, D., et al. (2007). Vascular-wall produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through platelet EP3 receptors. Journal of Experimental Medicine, 204(2), 311–320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Gresele, P., Blockmans, D., Deckmyn, H., & Vermylen, J. (1988). Adenylate cyclase activation determines the effect of thromboxane synthase inhibitors on platelet aggregation in vitro. Comparison of platelets from responders and nonresponders. Journal of Pharmacological and Experimental Therapeutics, 246(1), 301–307.

    CAS  Google Scholar 

  155. Singh, J., Zeller, W., Zhou, N., et al. (2009). Antagonists of the EP3 receptor for prostaglandin E2 are novel antiplatelet agents that do not prolong bleeding. ACS Chemical Biology, 4(2), 115–126.

    Article  CAS  PubMed  Google Scholar 

  156. Fox, S. C., May, J. A., Johnson, A., et al. (2013). Effects on platelet function of an EP3 receptor antagonist used alone and in combination with a P2Y12 antagonist both in vitro and ex vivo in human volunteers. Platelets, 24(5), 392–400.

    Article  CAS  PubMed  Google Scholar 

  157. Honn, K. V., Cicone, B., & Skoff, A. (1981). Prostacyclin: a potent antimetastatic agent. Science, 212(4500), 1270–1272.

    Article  CAS  PubMed  Google Scholar 

  158. Dogne, J. M., Hanson, J., & Pratico, D. (2005). Thromboxane, prostacyclin and isoprostanes: therapeutic targets in atherogenesis. Trends in Pharmacological Science, 26(12), 639–644.

    Article  CAS  Google Scholar 

  159. Fetalvero, K. M., Martin, K. A., & Hwa, J. (2007). Cardioprotective prostacyclin signaling in vascular smooth muscle. Prostaglandins and Other Lipid Mediators, 82(1–4), 109–118.

    Article  CAS  PubMed  Google Scholar 

  160. Keith, R. L., & Geraci, M. W. (2006). Prostacyclin in lung cancer. J Thoracic Oncology, 1(6), 503–505.

    Article  Google Scholar 

  161. Grommes, C., Landreth, G. E., & Heneka, M. T. (2004). Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncology, 5(7), 419–429.

    Article  CAS  PubMed  Google Scholar 

  162. Nemenoff, R. A., Meyer, A. M., Hudish, T. M., et al. (2008). Prostacyclin prevents murine lung cancer independent of the membrane receptor by activation of peroxisomal proliferator-activated receptor gamma. Cancer Prevention Research, 1(5), 349–356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. He, P., Borland, M. G., Zhu, B., et al. (2008). Effect of ligand activation of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) in human lung cancer cell lines. Toxicology, 254(1–2), 112–117 26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Pedchenko, T. V., Gonzalez, A. L., Wang, D., DuBois, R. N., & Massion, P. P. (2008). Peroxisome proliferator-activated receptor beta/delta expression and activation in lung cancer. American Journal of Respiratory Cell and Molecular Biology, 39(6), 689–696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Menter, D. G., Onoda, J. M., Taylor, J. D., & Honn, K. V. (1984). Effects of prostacyclin on tumor cell-induced platelet aggregation. Cancer Research, 44(2), 450–456.

    CAS  PubMed  Google Scholar 

  166. Menter, D. G., Onoda, J. M., Moilanen, D., Sloane, B. F., Taylor, J. D., & Honn, K. V. (1987). Inhibition by prostacyclin of the tumor cell-induced platelet release reaction and platelet aggregation. Journal of the National Cancer Institute, 78(5), 961–969.

    CAS  PubMed  Google Scholar 

  167. Honn, V. H., Cicone, B., & Skoff, A. (1980). Prostacyclin: a potent antimetastatic agent. Science, 212(4500), 1270–1272.

    Article  Google Scholar 

  168. Cuneo, K. C., Fu, A., Osusky, K. L., & Geng, L. (2007). Effects of vascular endothelial growth factor receptor inhibitor SU5416 and prostacyclin on murine lung metastasis. Anti-Cancer Drugs, 18(3), 349–355.

    Article  CAS  PubMed  Google Scholar 

  169. Keith, R. L., Miller, Y. E., Hoshikawa, Y., et al. (2002). Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. Cancer Research, 62(3), 734–740.

    CAS  PubMed  Google Scholar 

  170. Keith, R. L., Miller, Y. E., Hudish, T. M., et al. (2004). Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice. Cancer Research, 64(16), 5897–5904.

    Article  CAS  PubMed  Google Scholar 

  171. Honn, K. V., Meyer, J., Neagos, G., Henderson, T., Westley, C., & Ratanatharathorn, V. (1982). Control of tumor growth and metastasis with prostacyclin and thromboxane synthetase inhibitors: evidence for a new antitumor and antimetastatic agent (BAY G 6575). In G. A. Jamieson (Ed.), Interaction of platelets and tumor cells (pp. 295–331). New York: Alan R. Uss.

    Google Scholar 

  172. Bren-Mattison, Y., Van Putten, V., Chan, D., Winn, R., Geraci, M. W., & Nemenoff, R. A. (2005). Peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC). Oncogene, 24, 1412–1422.

    Article  CAS  PubMed  Google Scholar 

  173. Keith, R. L., Blatchford, P. J., Kittelson, J., et al. (2011). Oral iloprost improves endobronchial dysplasia in former smokers. Cancer Prevention Research, 4(6), 793–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Mascaux, C., Feser, W. J., Lewis, M. T., et al. (2013). Endobronchial miRNAs as biomarkers in lung cancer chemoprevention. Cancer Prevention Research, 6(2), 100–108.

    Article  CAS  PubMed  Google Scholar 

  175. Gibbins, J. M., Okuma, M., Farndale, R., Barnes, M., & Watson, S. P. (1997). Glycoprotein VI is the collagen receptor in platelets which underlies tyrosine phosphorylation of the Fc receptor gamma-chain. FEBS Letters, 413, 255–259.

    Article  CAS  PubMed  Google Scholar 

  176. Nieswandt, B., Bergmeier, W., Schulte, V., Rackebrandt, K., Gessner, J. E., & Zirngibl, H. (2000). Expression and function of the mouse collagen receptor glycoprotein VI is strictly dependent on its association with the FcRgamma chain. Journal of Biological Chemistry, 275(31), 23998–24002.

    Article  CAS  PubMed  Google Scholar 

  177. Nieswandt, B., Schulte, V., Bergmeier, W., et al. (2001). Long-term antithrombotic protection by in vivo depletion of platelet glycoprotein VI in mice. Journal of Experimental Medicine, 193(4), 459–469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Nieswandt, B., Brakebusch, C., Bergmeier, W., et al. (2001). Glycoprotein VI but not alpha2beta1 integrin is essential for platelet interaction with collagen. EMBO Journal, 20(9), 2120–2130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Clemetson, J. M., Polgar, J., Magnenat, E., Wells, T. N., & Clemetson, K. J. (1999). The platelet collagen receptor glycoprotein VI is a member of the immunoglobulin superfamily closely related to FcalphaR and the natural killer receptors. Journal of Biological Chemistry, 274(8), 29019–29024.

    Article  CAS  PubMed  Google Scholar 

  180. Jandrot-Perrus, M., Busfield, S., Lagrue, A. H., et al. (2000). Cloning, characterization, and functional studies of human and mouse glycoprotein VI: a platelet-specific collagen receptor from the immunoglobulin superfamily. Blood, 96(5), 1798–1807.

    CAS  PubMed  Google Scholar 

  181. Moroi, M., Jung, S. M., Okuma, M., & Shinmyozu, K. (1989). A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion. Journal of Clinical Investigation, 84(5), 1440–1445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Watson, S. P., Asazuma, N., Atkinson, B., et al. (2001). The role of ITAM- and ITIM-coupled receptors in platelet activation by collagen. Thrombosis and Haemostasis, 86, 276–288.

    CAS  PubMed  Google Scholar 

  183. Jain, S., Russell, S., & Ware, J. (2009). Platelet glycoprotein VI facilitates experimental lung metastasis in syngenic mouse models. Journal of Thrombosis and Haemostasis, 7(10), 1713–1717.

    Article  CAS  PubMed  Google Scholar 

  184. Ungerer, M., Rosport, K., Bultmann, A., et al. (2011). Novel antiplatelet drug revacept (dimeric glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans. Circulation, 123(17), 891–1899.

    Article  CAS  Google Scholar 

  185. Dovizio, M., Maier, T. J., Alberti, S., et al. (2013). Pharmacological inhibition of platelet–tumor cell cross-talk prevents platelet-induced overexpression of cyclooxygenase-2 in HT29 human colon carcinoma cells. Molecular Pharmacology, 84(1), 25–40.

    Article  CAS  PubMed  Google Scholar 

  186. Nangia-Makker, P., Balan, V., & Raz, A. (2008). Regulation of tumor progression by extracellular galectin-3. Cancer Microenvironment, 1(1), 43–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Coughlin, S. R. (2000). Thrombin signalling and protease-activated receptors. Nature, 407(6801), 258–264.

    Article  CAS  PubMed  Google Scholar 

  188. Krishnaswamy, S. (2013). The transition of prothrombin to thrombin. Journal of Thrombosis and Haemostasis, 11(Suppl 1), 265–276.

    Article  PubMed  PubMed Central  Google Scholar 

  189. Daniel, T., Gibbs, V. C., Milfay, D., et al. (1986). Thrombin stimulates c-sis gene expression in microvascular endothelial cells. Journal of Biological Chemistry, 261(21), 9579–9582.

    CAS  PubMed  Google Scholar 

  190. DeMichele, M., & Minnear, F. (1992). Modulation of vascular endothelial permeability by thrombin. Seminars in Thrombosis and Hemostasis, 18(3), 287–295.

    Article  CAS  PubMed  Google Scholar 

  191. Wojtukiewicz, M. Z., Tang, D. G., Ciarelli, J. J., et al. (1993). Thrombin increases the metastatic potential of tumor cells. International Journal of Cancer, 54(5), 793–806.

    Article  CAS  PubMed  Google Scholar 

  192. Nierodzik, M., Kajumo, F., & Karpatkin, S. (1992). Effect of thrombin treatment of tumor cells on adhesion of tumor cells to platelets in vitro and metastasis in vivo. Cancer Research, 52(12), 3267–3272.

    CAS  PubMed  Google Scholar 

  193. Chen, L. B., & Buchanan, J. M. (1975). Mitogenic activity of blood components. I. Thrombin and prothrombin. Proceedings of the National Academy of Science U S A, 72(1), 131–135.

    Article  CAS  Google Scholar 

  194. Szaba, F. M., & Smiley, S. T. (2002). Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo. Blood, 99, 1053–1059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Sugama, Y., Tiruppathi, C., Offakidevi, K., Andersen, T. T., Fenton 2nd, J. W., & Malik, A. B. (1992). Thrombin-induced expression of endothelial P-selectin and intercellular adhesion molecule-1: a mechanism for stabilizing neutrophil adhesion. Journal of Cell Biology, 119(4), 935–944.

    Article  CAS  PubMed  Google Scholar 

  196. Chiang, H. S., Yang, R. S., & Huang, T. F. (1996). Thrombin enhances the adhesion and migration of human colon adenocarcinoma cells via increased beta 3-integrin expression on the tumour cell surface and their inhibition by the snake venom peptide, rhodostomin. British Journal of Cancer, 73(7), 902–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Radjabi, A. R., Sawada, K., Jagadeeswaran, S., et al. (2008). Thrombin induces tumor invasion through the induction and association of matrix metalloproteinase-9 and beta1-integrin on the cell surface. Journal of Biological Chemistry, 283(5), 2822–2834.

    Article  CAS  PubMed  Google Scholar 

  198. Nierodzik, M. L., & Karpatkin, S. (2006). Thrombin induces tumor growth, metastasis, and angiogenesis: evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell, 110(5), 355–362.

    Article  Google Scholar 

  199. Coughlin, S. R. (2005). Protease-activated receptors in hemostasis, thrombosis and vascular biology. Journal of Thrombosis and Haemostasis, 3(8), 1800–1814.

    Article  CAS  PubMed  Google Scholar 

  200. Huang, Z., Miao, X., Luan, Y., et al. (2015). PAR1-stimulated platelet releasate promotes angiogenic activities of endothelial progenitor cells more potently than PAR4-stimulated platelet releasate. Thrombosis and Haemostasis, 13(3), 465–476.

    Article  CAS  Google Scholar 

  201. Sedda, S., Marafini, I., Caruso, R., Pallone, F., & Monteleone, G. (2014). Proteinase activated-receptors-associated signaling in the control of gastric cancer. World Journal of Gastroenterology, 20(34), 11977–11984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Albrektsen, T., Sorensen, B. B., Hjorto, G. M., Fleckner, J., Rao, L. V., & Petersen, L. C. (2007). Transcriptional program induced by factor VIIa tissue factor, PAR1 and PAR2 in MDA-MB-231 cells. Journal of Thrombosis and Haemostasis, 5(8), 1588–1597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Zhou, W., Hashimoto, K., Goleniewska, K., et al. (2007). Prostaglandin I2 analogs inhibit proinflammatory cytokine production and T cell stimulatory function of dendritic cells. Journal of Immunology, 178(2), 702–710.

    Article  CAS  Google Scholar 

  204. Otsuki, T., Fujimoto, D., Hirono, Y., Goi, T., & Yamaguchi, A. (2014). Thrombin conducts epithelial mesenchymal transition via protease activated receptor 1 in human gastric cancer. International Journal of Oncology, 45(6), 2287–2294.

    CAS  PubMed  Google Scholar 

  205. Fujimoto, D., Hirono, Y., Goi, T., Katayama, K., Matsukawa, S., & Yamaguchi, A. (2010). The activation of proteinase-activated receptor-1 (PAR1) mediates gastric cancer cell proliferation and invasion. Biomedical Central Cancer, 10, 443–458.

    Google Scholar 

  206. Uzunoglu, F. G., Yavari, N., Bohn, B. A., et al. (2013). C-X-C motif receptor 2, endostatin and proteinase-activated receptor 1 polymorphisms as prognostic factors in NSCLC. Lung Cancer, 81(1), 123–129.

    Article  PubMed  Google Scholar 

  207. Kaufmann, R., Junker, U., Junker, K., et al. (2002). The serine proteinase thrombin promotes migration of human renal carcinoma cells by a PKA-dependent mechanism. Cancer Letters, 180(2), 183–190.

    Article  CAS  PubMed  Google Scholar 

  208. Tsopanoglou, N. E., & Maragoudakis, M. E. (2004). Role of thrombin in angiogenesis and tumor progression. Seminars in Thrombosis and Hemostasis, 30(1), 63–69.

    Article  CAS  PubMed  Google Scholar 

  209. Wojtukiewicz, M. Z., Tang, D. G., Nelson, K. K., Walz, D. A., Diglio, C. A., & Honn, K. V. (1992). Thrombin enhances tumor cell adhesive and metastatic properties via increased alpha IIb beta 3 expression on the cell surface. Thrombosis Research, 68(3), 233–245.

    Article  CAS  PubMed  Google Scholar 

  210. Zhu, Q., Luo, J., Wang, T., Ren, J., Hu, K., & Wu, G. (2012). The activation of protease-activated receptor 1 mediates proliferation and invasion of nasopharyngeal carcinoma cells. Oncology Reports, 28(1), 255–261.

    CAS  PubMed  Google Scholar 

  211. Even-Ram, S. C., Maoz, M., et al. (2001). Tumor cell invasion is promoted by activation of protease activated receptor-1 in cooperation with the alpha vbeta 5 integrin. Journal of Biological Chemistry, 276(14), 10952–10962.

    Article  CAS  PubMed  Google Scholar 

  212. Bai, S. Y., Xu, N., Chen, C., Song, Y. L., Hu, J., & Bai, C. X. (2015). Integrin αvβ5 as a biomarker for the assessment of nonsmall cell lung cancer metastasis and overall survival. Clinical Respiratory Journal, 9(4), 457–467.

    Article  CAS  PubMed  Google Scholar 

  213. Fujimoto, D., Hirono, Y., Goi, T., Katayama, K., & Yamaguchi, A. (2008). Prognostic value of protease-activated receptor-1 (PAR-1) and matrix metalloproteinase-1 (MMP-1) in gastric cancer. Anticancer Research, 28(2A), 847–854.

    CAS  PubMed  Google Scholar 

  214. Boire, A., Covic, L., Agarwal, A., Jacques, S., Sherifi, S., & Kuliopulos, A. (2005). PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell, 120(3), 303–313.

    Article  CAS  PubMed  Google Scholar 

  215. Nierodzik, M., Plotkin, A., Kajumo, F., & Karpatkin, S. (1991). Thrombin stimulates tumor-platelet adhesion in vitro and metastasis in vivo. Journal of Clinical Investigation, 87(1), 229–236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Wojtukiewicz, M. Z., Tang, D. G., Ben-Josef, E., Renaud, C., Walz, D. A., & Honn, K. V. (1995). Solid tumor cells express functional “tethered ligand” thrombin receptor. Cancer Research, 55(3), 698–704.

    CAS  PubMed  Google Scholar 

  217. Nierodzik, M. L., Klepfish, A., & Karpatkin, S. (1995). Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastasis in vivo. Thrombosis and Haemostasis, 74(1), 282–290.

    CAS  PubMed  Google Scholar 

  218. Huang, Y. Q., Li, J.-J., Hu, L., & Karpatkin, S. (2002). Thrombin induces the synthesis of VEGF and angiopoietin-2 (Ang-2). Blood, 99(5), 1646–1650.

    Article  CAS  PubMed  Google Scholar 

  219. Mohle, R., Green, D., Moore, M., Nachman, R., & Rafii, S. (1997). Constitutive production and thrombin-induced release of VEGF by human megakaryocytes and platelets. Proceeding of the National Academy of Sciences USA, 94(2), 663–668.

    Article  CAS  Google Scholar 

  220. Li, J.-J., Huang, Y.-Q., Basch, R., & Karpatkin, S. (2001). Thrombin induces the release of angiopoietin-1 from platelets. Thrombosis and Haemostasis, 85(2), 204–206.

    CAS  PubMed  Google Scholar 

  221. Belting, M., Dorrell, M. I., Sandgren, S., et al. (2004). Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nature Medicine, 10(5), 502–509.

    Article  CAS  PubMed  Google Scholar 

  222. Trivedi, V., Boire, A., Tchernychev, B., et al. (2009). Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell, 137(2), 332–343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Sebastiano, M., Momi, S., Falcinelli, E., Bury, L., Hoylaerts, M. F., & Gresele, P. (2017). A novel mechanism regulating human platelet activation by MMP-2-mediated PAR1 biased signaling. Blood, 129(7), 883–895.

    Article  CAS  PubMed  Google Scholar 

  224. Jurasz, P., Sawicki, G., Duszyk, M., et al. (2001). Matrix metalloproteinase 2 in tumor cell-induced platelet aggregation: regulation by nitric oxide. Cancer Research, 61(1), 376–382.

    CAS  PubMed  Google Scholar 

  225. Martin, C., Mahon, G., Klinger, M. B., et al. (2001). The thrombin receptor, PAR-1, causes transformation by activation of Rho-mediated signaling pathways. Oncogene, 20(16), 1953–1963.

    Article  CAS  PubMed  Google Scholar 

  226. Nierodzik, M. L., & Karpatkin, S. (2006). Thrombin induces tumor growth, metastasis, and angiogenesis: evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell, 10(5), 355–362.

    Article  CAS  PubMed  Google Scholar 

  227. Even-Ram, S., Uziely, B., Cohen, P., et al. (1998). Thrombin receptor overexpression in malignant and physiological invasion processes. Nature Medicine, 4(8), 909–914.

    Article  CAS  PubMed  Google Scholar 

  228. Bar-Shavit, R., Turm, H., Salah, Z., Maoz, M., Cohen, I., Weiss, E., et al. (2011). PAR1 plays a role in epithelial malignancies: transcriptional regulation and novel signaling pathway. International Union of Biochemistry and Molecular Biology Life, 63(6), 397–402.

    Article  CAS  PubMed  Google Scholar 

  229. Yin, Y. J., Salah, Z., Grisaru-Granovsky, S., et al. (2003). Human protease-activated receptor-1 expression in malignant epithelia: a role in invasiveness. Ateriosclerosis Thrombosis and Vascular Biology, 23(6), 940–944.

    Article  CAS  Google Scholar 

  230. Yin, Y. J., Salah, Z., Grisaru-Granovsky, S., et al. (2003). Oncogenic transformation induces tumor angiogenesis: a role for PAR1 activation. Federation of American Societies for Experimental Biology Journal, 17(2), 163–174.

    Article  CAS  PubMed  Google Scholar 

  231. Zigler, M., Kamiya, T., Brantley, E. C., Villares, G. J., & Bar-Eli, M. (2011). PAR-1 and thrombin: the ties that bind the microenvironment to melanoma metastasis. Cancer Research, 71(21), 6561–6566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Morris, D. R., Ding, Y., Ricks, T. K., Gullapalli, A., Wolfe, B. L., & Trejo, J. (2006). Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells. Cancer Research, 66(1), 307–314.

    Article  CAS  PubMed  Google Scholar 

  233. Tsopanoglou, N. E., & Maragoudakis, M. E. (2007). Inhibition of angiogenesis by small-molecule antagonists of protease-activated receptor-1. Seminars in Thrombosis and Hemostasis, 33(7), 680–687.

    Article  CAS  PubMed  Google Scholar 

  234. Zania, P., Kritikou, S., Flordellis, C. S., Maragoudakis, M. E., & Tsopanoglou, N. E. (2006). Blockade of angiogenesis by small molecule antagonists to protease-activated receptor-1: association with endothelial cell growth suppression and induction of apoptosis. Journal of Pharmacology and Experimental Therapy, 318(1), 246–254.

    Article  CAS  Google Scholar 

  235. Gurbel, P. A., Bliden, K. P., Turner, S. E., et al. (2016). Cell-penetrating pepducin therapy targeting PAR1 in subjects with coronary artery disease. Arterioscleriosclerosis Thrombosis and Vascular Biology, 36(1), 189–197.

    CAS  Google Scholar 

  236. Yang, E., Boire, A., Agarwal, A., et al. (2009). Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt survival pathways in breast cancer cells and suppresses tumor survival and metastasis. Cancer Research, 69(15), 6223–6231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Cisowski, J., O'Callaghan, K., Kuliopulos, A., et al. (2011). Targeting protease-activated receptor-1 with cell-penetrating pepducins in lung cancer. American Journal of Pathology, 179(1), 513–523.

  238. Agarwal, A., Covic, L., Sevigny, L. M., Kaneider, N. C., Lazarides, K., Azabdaftari, G., et al. (2008). Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer. Molecular Cancer Therapeutics, 7(9), 2746–2757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Justus, C. R., & Yang, L. V. (2015). GPR4 decreases B16F10 melanoma cell spreading and regulates focal adhesion dynamics through the G13/Rho signaling pathway. Experimental Cell Research, 334(1), 100–113.

    Article  CAS  PubMed  Google Scholar 

  240. Bian, D., Mahanivong, C., Yu, J., et al. (2006). The G12/13-RhoA signaling pathway contributes to efficient lysophosphatidic acid-stimulated cell migration. Oncogene, 25(15), 2234–2244.

    Article  CAS  PubMed  Google Scholar 

  241. Lan, T., Wang, H., Zhang, Z., et al. (2017). Downregulation of β-arrestin 1 suppresses glioblastoma cell growth and glycolysis via inhibition of Src signaling. Experimental Cell Research, 4827(17), 30251–30253.

    Google Scholar 

  242. Duan, X., Kong, Z., Liu, Y., et al. (2015). β-Arrestin2 contributes to cell viability and proliferation via the down-regulation of FOXO1 in castration-resistant prostate cancer. Journal of Cellular Physiology, 230(10), 2371–2381.

    Article  CAS  PubMed  Google Scholar 

  243. Kotula, J. W., Sun, J., Li, M., et al. (2014). Targeted disruption of β-arrestin 2-mediated signaling pathways by aptamer chimeras leads to inhibition of leukemic cell growth. PloS One, 9(4), e93441.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  244. Xu, P., Zuo, H., Chen, B., et al. (2017). Doxorubicin-loaded platelets as a smart drug delivery system: an improved therapy for lymphoma. Scientific Reports, 7, 42632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Sarkar, S., Alam, M. A., Shaw, J., & Dasgupta, A. K. (2013). Drug delivery using platelet cancer cell interaction. Pharmacological Research, 30(11), 2785–2794.

    Article  CAS  Google Scholar 

  246. Xu, P., Zuo, H., Zhou, R., et al. (2017). Doxorubicin-loaded platelets conjugated with anti-CD22 mAbs: a novel targeted delivery system for lymphoma treatment with cardiopulmonary avoidance. Oncotarget. doi:10.18632/oncotarget.16871.

  247. Li, J., Sharkey, C. C., Wun, B., Liesveld, J. L., & King, M. R. (2016). Genetic engineering of platelets to neutralize circulating tumor cells. Journal of Controlled Release, 228, 38–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Li, J., Ai, Y., Wang, L., et al. (2016). Targeted drug delivery to circulating tumor cells via platelet membrane-functionalized particles. Biomaterials, 76, 52–65.

    Article  CAS  PubMed  Google Scholar 

  249. Hu, Q., Quian, C., Sun, W., et al. (2016). Engineered nanoplatelets for enhanced treatment of multiple myeloma and thrombus. Advanced Materials, 28(43), 9573–9580.

  250. Żmigrodzka, M., Guzera, M., Miśkiewicz, A., Jagielski, D., & Winnicka, A. (2016). The biology of extracellular vesicles with focus on platelet microparticles and their role in cancer development and progression. Tumour Biology, 37(11), 14391–14401.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  251. Amison, R., Page, C., & Pitchford, S. C. (2012). Pharmacological modulation of the inflammatory actions of platelets. Handbook of Experimental Pharmacology, 210, 447–468.

    Article  CAS  Google Scholar 

  252. Carboni, E., Tschudi, K., Nam, J., Lu, X., & Ma, A. W. (2014). Particle margination and its implications on intravenous anticancer drug delivery. AAPS PharmSciTech, 15(3), 762–771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Wang, C., et al. (2017). In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy. Nature Biomedical Engineering, 1, 0011. doi:10.1038/s41551-016-0011.

    Article  Google Scholar 

  254. Gresele, P., Momi, S., Pitchford, S. C., & Page, C. P. (2008). Platelets in respiratory disorders and inflammatory conditions. In P. Gresele, V. Fuster, J. A. Lòpez, C. P. Page, & J. Vermylen (Eds.), Platelets in hematologic and cardiovascular disorders, A clinical handbook (pp. 323–340). Cambridge, UK: Cambridge University Press.

    Google Scholar 

  255. Gresele, P., Falcinelli, E., & Momi, S. (2008). Potentiation and priming of platelet activation: a potential target for antiplatelet therapy. Trends in Pharmacological Sciences, 29(7), 352–360.

    Article  CAS  PubMed  Google Scholar 

  256. Menter, D. G., Davis, J. S., Tucker, S. C., et al. (2017). Platelets: “first responders” in cancer progression and metastasis. In P. Gresele, N. Kleiman, J. A. Lopez, & C. P. Page (Eds.), Platelets in thrombotic and non-thrombotic disorders (Vol. 2, pp. 1111–1132). Switzerland: Springer, Cham.

    Chapter  Google Scholar 

  257. Ware, J., & Post, S. R. (2017). Platelets and inflammatory disorders of connective tissue. In P. Gresele, N. Kleiman, J. A. Lopez, & C. P. Page (Eds.), Platelet in thrombotic and non-thrombotic disorders (Vol. 2, pp. 1133–1137). Switzerland: Springer, Cham.

    Chapter  Google Scholar 

  258. Momi, S., Pitchford, S. C., Gresle, P., & Page, C. P. (2017). Platelets and airway diseases. In P. Gresele, N. Kleiman, J. A. Lopez, & C. P. Page (Eds.), Platelet in thrombotic and non-thrombotic disorders (Vol. 2, pp. 1149–1168). Switzerland: Springer, Cham.

    Chapter  Google Scholar 

  259. Andre, P. (2017). Targeting intraplatelet signaling pathways as potential antithrombotic strategy. In P. Gresele, N. Kleiman, J. A. Lopez, & C. P. Page (Eds.), Platelet in thrombotic and non-thrombotic disorders (Vol. 2, pp. 1341–1360). Switzerland: Springer, Cham.

    Chapter  Google Scholar 

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Acknowledgments

The authors would like to thank Dr. S. Orsini for skilled editorial assistance. This work was supported in part by a grant to P.G. from H2020-FETOPEN-2014-CSA (CIRCLE, proposal # 665564).

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Gresele, P., Momi, S., Malvestiti, M. et al. Platelet-targeted pharmacologic treatments as anti-cancer therapy. Cancer Metastasis Rev 36, 331–355 (2017). https://doi.org/10.1007/s10555-017-9679-8

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