Skip to main content

Advertisement

SpringerLink
Log in

Platelets as crucial partners for tumor metastasis: from mechanistic aspects to pharmacological targeting

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Platelets are anucleated cells that circulate in the blood as sentinels of tissue integrity. In fact, they are rich in a plethora of proteins and other factors stored in different granules which they selectively release upon stimulation. Moreover, platelets synthesize a vast number of lipids and release various types of vesicles, including exosomes which are rich in genetic material. Platelets possess a central function to interact with other cell types, including inflammatory cells and cancer cells. Recent findings have enlightened the capacity of platelets to induce changes in the phenotype of cancer cells which acquire invasiveness thus enhancing their metastatic potential. Thus, it has been hypothesized that targeting the platelet may represent a novel strategy to prevent the development and progression of cancer. This is supported by the efficacy of the antiplatelet agent low-dose aspirin. Studies are ongoing to verify whether other antiplatelet agents share the anticancer effectiveness of aspirin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

AA:

Arachidonic acid

ADP:

Adenosine diphosphate

ATP:

Adenosine triphosphate

ATX:

Autotaxin

Bcl-3:

B-cell lymphoma 3-encoded protein

cAMP:

Cyclic adenosine monophosphate

CD40L:

CD40 ligand

CLEC:

C-type lectin-like receptor

COX:

Cyclooxygenase

CP:

Cancer procoagulant

cPGES:

Cytosolic PGE synthase

CRC:

Colorectal cancer

CRP:

Collagen-related peptide

EGF:

Epidermal growth factor

EMT:

Epithelial–mesenchymal transition

FA:

Fatty acid

FACL:

Fatty acid-CoA ligase

FcγRIIa:

Fcγ receptor IIa

GP:

Glycoprotein

GPCR:

G-protein coupled receptor

HETE:

Hydroxy-eicosatetraenoic acid

HIF:

Hypoxia-induced factor

HPETE:

Hydroperoxy-eicosatetraenoic acid

IL:

Interleukin

IP:

Prostaglandin I2 receptor

ITAM:

Immunoreceptor tyrosine-based activation motif

LMWH:

Low-molecular weight heparin

LOX:

Lipoxygenase

LPA:

Lysophosphatidic acid

mPGES:

Microsomal PGE synthase

MPs:

Microparticles

NK:

Natural killer

NSAID:

Nonsteroidal anti-inflammatory drug

OxPLs:

Oxidized phospholipids

PAR:

Protease-activated receptor

PC:

Phosphatidylcholine

PDGF:

Platelet-derived growth factor

PE:

Phosphatidylethanolamine

PF-4:

Platelet factor 4

PG:

Prostaglandin

PI3K:

Phosphoinositide 3-kinase

PL:

Phospholipid

PLA:

Phospholipase A

pS6:

S6 protein

PSGL-1:

P-selectin glycoprotein ligand-1

RCT:

Randomized clinical trial

RGD:

Arginylglycylaspartic acid

RhoGEF:

RhoGTPase nucleotide exchange factor

RNA:

Ribonucleic acid

Syk:

Spleen tyrosine kinase

TF:

Tissue factor

TGFβ:

Transforming growth factor β

TLR:

Toll-like receptor

TP:

Thromboxane A2 receptor

TX:

Thromboxane

TXAS:

Thromboxane A2 synthase

VASP:

Vasodilator-stimulated phosphoprotein

VEGF:

Vascular endothelial growth factor

VWF:

Von Willebrand factor

References

  1. Smittenaar CR, Petersen KA, Stewart K, Moitt N (2016) Cancer incidence and mortality projections in the UK until 2035. Br J Cancer 115:1147–1155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. World Health Organization (2009) WHO Report on the Global Tobacco Epidemic. Geneva, ISBN: 978 92 4 156391 8

  3. Després JP (2012) Body fat distribution and risk of cardiovascular disease: an update. Circulation 126(10):1301–1313

    Article  PubMed  Google Scholar 

  4. Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, Meade TW (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 

  5. Patrignani P, Patrono C (2016) Aspirin and cancer. J Am Coll Cardiol 68(9):967–976

    Article  CAS  PubMed  Google Scholar 

  6. Dovizio M, Alberti S, Guillem-Llobat P, Patrignani P (2014) Role of platelets in inflammation and cancer: novel therapeutic strategies. Basic Clin Pharmacol Toxicol 114(1):118–127

    Article  CAS  PubMed  Google Scholar 

  7. Best MG, Sol N, Kooi I, Tannous J, Westerman BA, Rustenburg F, Schellen P, Verschueren H, Post E, Koster J, Ylstra B, Ameziane N, Dorsman J, Smit EF, Verheul HM, Noske DP, Reijneveld JC, Nilsson RJ, Tannous BA, Wesseling P, Wurdinger T (2015) RNA-Seq of tumor-educated platelets enables blood-based pan-cancer, multiclass, and molecular pathway cancer diagnostics. Cancer Cell 28(5):666–676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nilsson RJ, Balaj L, Hulleman E, van Rijn S, Pegtel DM, Walraven M, Widmark A, Gerritsen WR, Verheul HM, Vandertop WP, Noske DP, Skog J, Würdinger T (2011) Blood platelets contain tumor-derived RNA biomarkers. Blood 118(13):3680–3683

    Article  PubMed  Google Scholar 

  9. Gawaz M, Langer H, May AE (2005) Platelets in inflammation and atherogenesis. J Clin Invest 115(12):3378–3384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Franco AT, Corken A, Ware J (2015) Platelets at the interface of thrombosis, inflammation, and cancer. Blood 126(5):582–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yan M, Jurasz P (2016) The role of platelets in the tumor microenvironment: from solid tumors to leukemia. Biochim Biophys Acta 1863(3):392–400

    Article  CAS  PubMed  Google Scholar 

  12. Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18(6):884–901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bibbins-Domingo K, U.S. Preventive Services Task Force (2016) Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 164:836–845

    Article  PubMed  Google Scholar 

  14. Steeg PS (2016) Targeting metastasis. Nat Rev Cancer 16(4):201–218

    Article  CAS  PubMed  Google Scholar 

  15. Gay LJ, Felding-Habermann B (2011) Contribution of platelets to tumour metastasis. Nat Rev Cancer 11(2):123–134

    Article  CAS  PubMed  Google Scholar 

  16. Diaz-Cano SJ (2012) Tumor heterogeneity: mechanisms and bases for a reliable application of molecular marker design. Int J Mol Sci 13(2):1951–2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kalluri R, Weinberg RA (2009) The basics of epithelial–mesenchymal transition. J Clin Invest 119(6):1420–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Talbot LJ, Bhattacharya SD, Kuo PC (2012) Epithelial–mesenchymal transition, the tumor microenvironment, and metastatic behavior of epithelial malignancies. Int J Biochem Mol Biol 3(2):117–136

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Tímár J, Tóvári J, Rásó E, Mészáros L, Bereczky B, Lapis K (2005) Platelet-mimicry of cancer cells: epiphenomenon with clinical significance. Oncology 69(3):185–201

    Article  PubMed  Google Scholar 

  20. Qiao L, Liang N, Zhang J, Xie J, Liu F, Xu D, Yu X, Tian Y (2015) Advanced research on vasculogenic mimicry in cancer. J Cell Mol Med 19(2):315–326

    Article  PubMed  PubMed Central  Google Scholar 

  21. Patel SR, Hartwig JH, Italiano JE Jr (2005) The biogenesis of platelets from megakaryocyte proplatelets. J Clin Invest 115(12):3348–3354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Norol F, Vitrat N, Cramer E, Guichard J, Burstein SA, Vainchenker W, Debili N (1998) Effects of cytokines on platelet production from blood and marrow CD34+ cells. Blood 91(3):830–843

    CAS  PubMed  Google Scholar 

  23. Michelson AD (2013) Platelets. Elsevier, London

    Google Scholar 

  24. Lhermusier T, Chap H, Payrastre B (2011) Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome. J Thromb Haemost 9(10):1883–1891

    Article  CAS  PubMed  Google Scholar 

  25. Cimmino G, Golino P (2013) Platelet biology and receptor pathways. J Cardiovasc Transl Res 6(3):299–309

    Article  PubMed  Google Scholar 

  26. White JG (1968) Tubular elements in platelet granules. Blood 32(1):148–156

    CAS  PubMed  Google Scholar 

  27. Harris JR (1991) Blood cell biochemestry. Springer Science + Business Media, New York

    Google Scholar 

  28. Fukuda M (1991) Lysosomal membrane glycoproteins. Structure, biosynthesis, and intracellular trafficking. J Biol Chem 266(32):21327–21330

    CAS  PubMed  Google Scholar 

  29. McNicol A, Israels SJ (1999) Platelet dense granules: structure, function and implications for haemostasis. Thromb Res 95(1):1–18

    Article  CAS  PubMed  Google Scholar 

  30. Fuentes QE, Fuentes QF, Andrés V, Pello OM, Font de Mora J, Palomo GI (2013) Role of platelets as mediators that link inflammation and thrombosis in atherosclerosis. Platelets 24(4):255–262

    Article  CAS  Google Scholar 

  31. Blair P, Flaumenhaft R (2009) Platelet alpha-granules: basic biology and clinical correlates. Blood Rev 23(4):177–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chatterjee M, Huang Z, Zhang W, Jiang L, Hultenby K, Zhu L, Hu H, Nilsson GP, Li N (2011) Distinct platelet packaging, release, and surface expression of proangiogenic and antiangiogenic factors on different platelet stimuli. Blood 117(14):3907–3911

    Article  CAS  PubMed  Google Scholar 

  33. Senior RM, Griffin GL, Huang JS, Walz DA, Deuel TF (1983) Chemotactic activity of platelet alpha granule proteins for fibroblasts. J Cell Biol 96(2):382–385

    Article  CAS  PubMed  Google Scholar 

  34. Hargett LA, Bauer NN (2013) On the origin of microparticles: from “platelet dust” to mediators of intercellular communication. Pulm Circ 3(2):329–340

    Article  PubMed  PubMed Central  Google Scholar 

  35. Bobrie A, Colombo M, Raposo G, Théry C (2011) Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 12(12):1659–1668

    Article  CAS  PubMed  Google Scholar 

  36. Mause SF, Weber C (2010) Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res 107(9):1047–1057

    Article  CAS  PubMed  Google Scholar 

  37. Zimmerman GA, Weyrich AS (2008) Signal-dependent protein synthesis by activated platelets: new pathways to altered phenotype and function. Arterioscler Thromb Vasc Biol 28(3):s17–s24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Weyrich AS, Dixon DA, Pabla R, Elstad MR, McIntyre TM, Prescott SM, Zimmerman GA (1998) Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets. Proc Natl Acad Sci USA 95(10):5556–5561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Evangelista V, Manarini S, Di Santo A, Capone ML, Ricciotti E, Di Francesco L, Tacconelli S, Sacchetti A, D’Angelo S, Scilimati A, Sciulli MG, Patrignani P (2006) De novo synthesis of cyclooxygenase-1 counteracts the suppression of platelet thromboxane biosynthesis by aspirin. Circ Res 98(5):593–595

    Article  CAS  PubMed  Google Scholar 

  40. Patrono C, Baigent C, Hirsh J, Roth G (2008) Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133(6 Suppl):199S–233S

    Article  CAS  PubMed  Google Scholar 

  41. Yang H, Lang S, Zhai Z, Li L, Kahr WH, Chen P, Brkić J, Spring CM, Flick MJ, Degen JL, Freedman J, Ni H (2009) Fibrinogen is required for maintenance of platelet intracellular and cell-surface P-selectin expression. Blood 114(2):425–436

    Article  CAS  PubMed  Google Scholar 

  42. Borsig L, Wong R, Feramisco J, Nadeau DR, Varki NM, Varki A (2001) Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci USA 98(6):3352–3357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Austrup F, Vestweber D, Borges E, Löhning M, Bräuer R, Herz U, Renz H, Hallmann R, Scheffold A, Radbruch A, Hamann A (1997) P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed tissues. Nature 385(6611):81–83

    Article  CAS  PubMed  Google Scholar 

  44. Tinoco R, Carrette F, Barraza ML, Otero DC, Magaña J, Bosenberg MW, Swain SL, Bradley LM (2016) PSGL-1 is an immune checkpoint regulator that promotes T cell exhaustion. Immunity 44(5):1190–1203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Macaulay IC, Carr P, Gusnanto A, Ouwehand WH, Fitzgerald D, Watkins NA (2005) Platelet genomics and proteomics in human health and disease. J Clin Invest 115(12):3370–3377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. McRedmond JP, Park SD, Reilly DF, Coppinger JA, Maguire PB, Shields DC, Fitzgerald DJ (2004) Integration of proteomics and genomics in platelets: a profile of platelet proteins and platelet-specific genes. Mol Cell Proteomics 3(2):133–144

    Article  CAS  PubMed  Google Scholar 

  47. Patrignani P, Patrono C (2015) Cyclooxygenase inhibitors: from pharmacology to clinical read-outs. Biochim Biophys Acta 1851(4):422–432

    Article  CAS  PubMed  Google Scholar 

  48. Patrignani P, Tacconelli S (2005) Isoprostanes and other markers of peroxidation in atherosclerosis. Biomarkers 10(Suppl 1):S24–S29

    Article  CAS  PubMed  Google Scholar 

  49. Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182

    Article  CAS  PubMed  Google Scholar 

  50. Hourani SM, Cusack NJ (1991) Pharmacological receptors on blood platelets. Pharmacol Rev 43(3):243–298

    CAS  PubMed  Google Scholar 

  51. Dorn GW 2nd, Becker MW (1993) Thromboxane A2 stimulated signal transduction in vascular smooth muscle. J Pharmacol Exp Ther 265(1):447–456

    CAS  PubMed  Google Scholar 

  52. Park JY, Pillinger MH, Abramson SB (2006) Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases. Clin Immunol 119(3):229–240

    Article  CAS  PubMed  Google Scholar 

  53. Smith JB, Willis AL (1970) Formation and release of prostaglandins by platelets in response to thrombin. Br J Pharmacol 40(3):545P–546P

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Song WL, Stubbe J, Ricciotti E, Alamuddin N, Ibrahim S, Crichton I, Prempeh M, Lawson JA, Wilensky RL, Rasmussen LM, Puré E, FitzGerald GA (2012) Niacin and biosynthesis of PGD2 by platelet COX-1 in mice and humans. J Clin Invest 122(4):1459–1468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Narumiya S, Sugimoto Y, Ushikubi F (1999) Prostanoid receptors: structures, properties, and functions. Physiol Rev 79(4):1193–1226

    CAS  PubMed  Google Scholar 

  56. Fabre JE, Nguyen M, Athirakul K, Coggins K, McNeish JD, Austin S, Parise LK, FitzGerald GA, Coffman TM, Koller BH (2001) Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation. J Clin Invest 107(5):603–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Grosser T, Fries S, FitzGerald GA (2006) Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 116(1):4–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhao L, Funk CD (2004) Lipoxygenase pathways in atherogenesis. Trends Cardiovasc Med 14(5):191–195

    Article  CAS  PubMed  Google Scholar 

  59. Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294(5548):1871–1875

    Article  CAS  PubMed  Google Scholar 

  60. Honn KV, Tang DG, Gao X, Butovich IA, Liu B, Timar J, Hagmann W (1994) 12-lipoxygenases and 12(S)-HETE: role in cancer metastasis. Cancer Metastasis Rev 13(3–4):365–396

    Article  CAS  PubMed  Google Scholar 

  61. Hamberg M, Samuelsson B (1974) Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc Natl Acad Sci USA 71(9):3400–3404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Morgan LT, Thomas CP, Kühn H, O’Donnell VB (2010) Thrombin-activated human platelets acutely generate oxidized docosahexaenoic-acid-containing phospholipids via 12-lipoxygenase. Biochem J 431(1):141–148

    Article  CAS  PubMed  Google Scholar 

  63. Ikei KN, Yeung J, Apopa PL, Ceja J, Vesci J, Holman TR, Holinstat M (2012) Investigations of human platelet-type 12-lipoxygenase: role of lipoxygenase products in platelet activation. J Lipid Res 53(12):2546–2559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yeung J, Holinstat M (2011) 12-lipoxygenase: a potential target for novel anti-platelet therapeutics. Cardiovasc Hematol Agents Med Chem 9(3):154–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Guo Y, Zhang W, Giroux C, Cai Y, Ekambaram P, Dilly AK, Hsu A, Zhou S, Maddipati KR, Liu J, Joshi S, Tucker SC, Lee MJ, Honn KV (2011) Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid. J Biol Chem 286(39):33832–33840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Aldrovandi M, O’Donnell VB (2013) Oxidized PLs and vascular inflammation. Curr Atheroscler Rep 15(5):323

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. O’Donnell VB (2011) Mass spectrometry analysis of oxidized phosphatidylcholine and phosphatidylethanolamine. Biochim Biophys Acta 1811(11):818–826

    Article  PubMed  CAS  Google Scholar 

  68. O’Donnell VB, Murphy RC (2012) New families of bioactive oxidized phospholipids generated by immune cells: identification and signaling actions. Blood 120(10):1985–1992

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Wang D, Dubois RN (2010) Eicosanoids and cancer. Nat Rev Cancer 10(3):181–193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Klampfl T, Bogner E, Bednar W, Mager L, Massudom D, Kalny I, Heinzle C, Berger W, Stättner S, Karner J, Klimpfinger M, Fürstenberger G, Krieg P, Marian B (2012) Up-regulation of 12(S)-lipoxygenase induces a migratory phenotype in colorectal cancer cells. Exp Cell Res 318(6):768–778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ozaki Y, Asazuma N, Suzuki-Inoue K, Berndt MC (2005) Platelet GPIb-IX-V-dependent signaling. J Thromb Haemost 3(8):1745–1751

    Article  CAS  PubMed  Google Scholar 

  72. Boulaftali Y, Hess PR, Kahn ML, Bergmeier W (2014) Platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling and vascular integrity. Circ Res 114(7):1174–1184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Nieswandt B, Watson SP (2003) Platelet–collagen interaction: is GPVI the central receptor? Blood 102(2):449–461

    Article  CAS  PubMed  Google Scholar 

  74. Watson SP, Auger JM, McCarty OJ, Pearce AC (2005) GPVI and integrin alphaIIb beta3 signaling in platelets. J Thromb Haemost 3(8):1752–1762

    Article  CAS  PubMed  Google Scholar 

  75. Dunne E, Spring CM, Reheman A, Jin W, Berndt MC, Newman DK, Newman PJ, Ni H, Kenny D (2012) Cadherin 6 has a functional role in platelet aggregation and thrombus formation. Arterioscler Thromb Vasc Biol 32(7):1724–1731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Cho J, Mosher DF (2006) Role of fibronectin assembly in platelet thrombus formation. J Thromb Haemost 4(7):1461–1469

    Article  CAS  PubMed  Google Scholar 

  77. Arneson MA, Hammerschmidt DE, Furcht LT, King RA (1980) A new form of Ehlers-Danlos syndrome. Fibronectin corrects defective platelet function. JAMA 244(2):144–147

    CAS  PubMed  Google Scholar 

  78. Santoro SA (1983) Inhibition of platelet aggregation by fibronectin. Biochem Biophys Res Commun 116(1):135–140

    Article  CAS  PubMed  Google Scholar 

  79. Moon DG, Kaplan JE, Mazurkewicz JE (1986) The inhibitory effect of plasma fibronectin on collagen-induced platelet aggregation. Blood 67(2):450–457

    CAS  PubMed  Google Scholar 

  80. Reheman A, Yang H, Zhu G, Jin W, He F, Spring CM, Bai X, Gross PL, Freedman J, Ni H (2009) Plasma fibronectin depletion enhances platelet aggregation and thrombus formation in mice lacking fibrinogen and von Willebrand factor. Blood 113(8):1809–1817

    Article  CAS  PubMed  Google Scholar 

  81. Gartner TK, Bennett JS (1985) The tetrapeptide analogue of the cell attachment site of fibronectin inhibits platelet aggregation and fibrinogen binding to activated platelets. J Biol Chem 260(22):11891–11894

    CAS  PubMed  Google Scholar 

  82. Ni H, Denis CV, Subbarao S, Degen JL, Sato TN, Hynes RO, Wagner DD (2000) Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 106(3):385–392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang Y, Reheman A, Spring CM, Kalantari J, Marshall AH, Wolberg AS, Gross PL, Weitz JI, Rand ML, Mosher DF, Freedman J, Ni H (2014) Plasma fibronectin supports hemostasis and regulates thrombosis. J Clin Invest 124(10):4281–4293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhi H, Rauova L, Hayes V, Gao C, Boylan B, Newman DK, McKenzie SE, Cooley BC, Poncz M, Newman PJ (2013) Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo. Blood 121(10):1858–1867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Woulfe DS (2005) Platelet G protein-coupled receptors in hemostasis and thrombosis. J Thromb Haemost 10:2193–2200

    Article  Google Scholar 

  86. Leger AJ, Covic L, Kuliopulos A (2006) Protease-activated receptors in cardiovascular diseases. Circulation 114(10):1070–1077

    Article  CAS  PubMed  Google Scholar 

  87. Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407(6801):258–264

    Article  CAS  PubMed  Google Scholar 

  88. Smyth SS, Woulfe DS, Weitz JI, Gachet C, Conley PB, Goodman SG, Roe MT, Kuliopulos A, Moliterno DJ, French PA, Steinhubl SR, Becker RC (2009) G-protein-coupled receptors as signaling targets for antiplatelet therapy. Arterioscler Thromb Vasc Biol 29(4):449–457

    Article  CAS  PubMed  Google Scholar 

  89. Fitzgerald DJ, Fitzgerald GA (2013) Historical lessons in translational medicine: cyclooxygenase inhibition and P2Y12 antagonism. Circ Res 112(1):174–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Schwarz UR, Geiger J, Walter U, Eigenthaler M (1999) Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets—definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost 82(3):1145–1152

    CAS  PubMed  Google Scholar 

  91. Hirata T, Ushikubi F, Kakizuka A, Okuma M, Narumiya S (1996) Two thromboxane A2 receptor isoforms in human platelets. Opposite coupling to adenylyl cyclase with different sensitivity to Arg60 to Leu mutation. J Clin Invest 97(4):949–956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Siehler S (2009) Regulation of RhoGEF proteins by G12/13-coupled receptors. Br J Pharmacol 158(1):41–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Paul BZ, Jin J, Kunapuli SP (1999) Molecular mechanism of thromboxane A(2)-induced platelet aggregation. Essential role for p2t(ac) and alpha(2a) receptors. J Biol Chem 274(41):29108–29114

    Article  CAS  PubMed  Google Scholar 

  94. Davì G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357(24):2482–2494

    Article  PubMed  Google Scholar 

  95. Xu XR, Zhang D, Oswald BE, Carrim N, Wang X, Hou Y, Zhang Q, Lavalle C, McKeown T, Marshall AH, Ni H (2016) Platelets are versatile cells: New discoveries in hemostasis, thrombosis, immune responses, tumor metastasis and beyond. Crit Rev Clin Lab Sci 53(6):409–430

    Article  CAS  PubMed  Google Scholar 

  96. Labelle M, Begum S, Hynes RO (2011) Direct signaling between platelets and cancer cells induces an epithelial–mesenchymal-like transition and promotes metastasis. Cancer Cell 20(5):576–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dovizio M, Maier TJ, Alberti S, Di Francesco L, Marcantoni E, Münch G, John CM, Suess B, Sgambato A, Steinhilber D, Patrignani P (2013) Pharmacological inhibition of platelet–tumor cell cross-talk prevents platelet-induced overexpression of cyclooxygenase-2 in HT29 human colon carcinoma cells. Mol Pharmacol 84(1):25–40

    Article  CAS  PubMed  Google Scholar 

  98. Guillem-Llobat P, Dovizio M, Bruno A, Ricciotti E, Cufino V, Sacco A, Grande R, Alberti S, Arena V, Cirillo M, Patrono C, FitzGerald GA, Steinhilber D, Sgambato A, Patrignani P (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 

  99. Wang D, Dubois RN (2010) The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene 29(6):781–788

    Article  CAS  PubMed  Google Scholar 

  100. Ungerer M, Rosport K, Bültmann A, Piechatzek R, Uhland K, Schlieper P, Gawaz M, Münch G (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):1891–1899

    Article  CAS  PubMed  Google Scholar 

  101. Battinelli EM, Markens BA, Kulenthirarajan RA, Machlus KR, Flaumenhaft R, Italiano JE Jr (2014) Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response. Blood 123:101–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Nierodzik ML, 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 

  103. Gale AJ, Gordon SG (2001) Update on tumor cell procoagulant factors. Acta Haematol 106(1–2):25–32

    Article  CAS  PubMed  Google Scholar 

  104. Mitrugno A, Williams D, Kerrigan SW, Moran N (2014) A novel and essential role for FcγRIIa in cancer cell-induced platelet activation. Blood 123(2):249–260

    Article  CAS  PubMed  Google Scholar 

  105. Mannori G, Crottet P, Cecconi O, Hanasaki K, Aruffo A, Nelson RM, Varki A, Bevilacqua MP (1995) Differential colon cancer cell adhesion to E-, P-, and L-selectin: role of mucin-type glycoproteins. Cancer Res 55(19):4425–4431

    CAS  PubMed  Google Scholar 

  106. Boukerche H, Berthier-Vergnes O, Tabone E, Doré JF, Leung LL, McGregor JL (1989) Platelet–melanoma cell interaction is mediated by the glycoprotein IIb–IIIa complex. Blood 74(2):658–663

    CAS  PubMed  Google Scholar 

  107. Nierodzik ML, Plotkin A, Kajumo F, Karpatkin S (1991) Thrombin stimulates tumor-platelet adhesion in vitro and metastasis in vivo. J Clin Invest 87(1):229–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Karpatkin S, Pearlstein E, Ambrogio C, Coller BS (1988) Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo. J Clin Invest 81(4):1012–1019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mammadova-Bach E, Zigrino P, Brucker C, Bourdon C, Freund M, De Arcangelis A, Abrams SI, Orend G, Gachet C, Mangin PH (2016) Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell-derived ADAM9. JCI Insight 1(14):e88245

    Article  PubMed  PubMed Central  Google Scholar 

  110. Gerrard JM (1001) Robinson P (1989) Identification of the molecular species of lysophosphatidic acid produced when platelets are stimulated by thrombin. Biochim Biophys Acta 3:282–285

    Google Scholar 

  111. Williams JR, Khandoga AL, Goyal P, Fells JI, Perygin DH, Siess W, Parrill AL, Tigyi G, Fujiwara Y (2009) Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation. J Biol Chem 284(25):17304–17319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mills GB, Moolenaar WH (2003) The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer 3(8):582–591

    Article  CAS  PubMed  Google Scholar 

  113. Boucharaba A, Serre CM, Grès S, Saulnier-Blache JS, Bordet JC, Guglielmi J, Clézardin P, Peyruchaud O (2004) Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J Clin Invest 114(12):1714–1725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Boucharaba A, Serre CM, Guglielmi J, Bordet JC, Clézardin P, Peyruchaud O (2006) The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases. Proc Natl Acad Sci USA 103(25):9643–9648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Leblanc R, Lee SC, David M, Bordet JC, Norman DD, Patil R, Miller D, Sahay D, Ribeiro J, Clézardin P, Tigyi GJ, Peyruchaud O (2014) Interaction of platelet-derived autotaxin with tumor integrin αVβ3 controls metastasis of breast cancer cells to bone. Blood 124(20):3141–3150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Burkhalter RJ, Westfall SD, Liu Y, Stack MS (2015) Lysophosphatidic acid initiatesepithelial to mesenchymal transition and induces β-catenin-mediated transcription in epithelial ovarian carcinoma. J Biol Chem 290(36):22143–22154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ha JH, Ward JD, Radhakrishnan R, Jayaraman M, Song YS, Dhanasekaran DN (2016) Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus. Oncotarget 7(25):37664–37679

    Article  PubMed  PubMed Central  Google Scholar 

  118. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW (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 

  119. Rothwell PM, Price JF, Fowkes FG, Zanchetti A, Roncaglioni MC, Tognoni G, Lee R, Belch JF, Wilson M, Mehta Z, Meade TW (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 

  120. Simmons DL, Botting RM, Hla T (2004) Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56(3):387–437

    Article  CAS  PubMed  Google Scholar 

  121. Loll PJ, Picot D, Garavito RM (1995) The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat Struct Biol 2(8):637–643

    Article  CAS  PubMed  Google Scholar 

  122. Lecomte M, Laneuville O, Ji C, DeWitt DL, Smith WL (1994) Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin. J Biol Chem 269(18):13207–13215

    CAS  PubMed  Google Scholar 

  123. Patrignani P, Filabozzi P, Patrono C (1982) Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 69(6):1366–1372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Patrignani P, Tacconelli S, Piazuelo E, Di Francesco L, Dovizio M, Sostres C, Marcantoni E, Guillem-Llobat P, Del Boccio P, Zucchelli M, Patrono C, Lanas A (2014) Reappraisal of the clinical pharmacology of low-dose aspirin by comparing novel direct and traditional indirect biomarkers of drug action. J Thromb Haemost 12(8):1320–1330

    Article  CAS  PubMed  Google Scholar 

  125. Patrono C, Patrignani P, García Rodríguez LA (2001) Cyclooxygenase-selective inhibition of prostanoid formation: transducing biochemical selectivity into clinical read-outs. J Clin Invest 108(1):7–13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Di Francesco L, López Contreras LA, Sacco A, Patrignani P (2015) New insights into the mechanism of action of aspirin in the prevention of colorectal neoplasia. Curr Pharm Des 21(35):5116–5126

    Article  PubMed  CAS  Google Scholar 

  127. Patrignani P, Sacco A, Sostres C, Bruno A, Dovizio M, Piazuelo E, Di Francesco L, Contursi A, Zucchelli M, Schiavone S, Tacconelli S, Patrono C, Lanas A (2017) Low-dose aspirin acetylates cyclooxygenase-1 in human colorectal mucosa: implications for the chemoprevention of colorectal cancer. Clin Pharmacol Ther (Epub ahead of print)

  128. Ruvinsky I, Sharon N, Lerer T, Cohen H, Stolovich-Rain M, Nir T, Dor Y, Zisman P, Meyuhas O (2005) Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev 19(18):2199–2211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Cattaneo M (2010) New P2Y(12) inhibitors. Circulation 121(1):171–179

    Article  PubMed  Google Scholar 

  130. Wang Y, Sun Y, Li D, Zhang L, Wang K, Zuo Y, Gartner TK, Liu J (2013) Platelet P2Y12 is involved in murine pulmonary metastasis. PLoS One 8(11):e80780

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Sitia G, Aiolfi R, Di Lucia P, Mainetti M, Fiocchi A, Mingozzi F, Esposito A, Ruggeri ZM, Chisari FV, Iannacone M, Guidotti LG (2012) Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci USA 109(32):E2165–E2172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Nierodzik ML, 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. Thromb Haemost 74(1):282–290

    CAS  PubMed  Google Scholar 

  133. Amirkhosravi A, Mousa SA, Amaya M, Blaydes S, Desai H, Meyer T, Francis JL (2003) Inhibition of tumor cell-induced platelet aggregation and lung metastasis by the oral GpIIb/IIIa antagonist XV454. Thromb Haemost 90(3):549–554

    CAS  PubMed  Google Scholar 

  134. Italiano JE Jr, Richardson JL, Patel-Hett S, Battinelli E, Zaslavsky A, Short S, Ryeom S, Folkman J, Klement GL (2008) Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 111(3):1227–1233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Dovizio M, Sacco A, Patrignani P (2017) Curbing tumorigenesis and malignant progression through the pharmacological control of the wound healing process. Vasc Pharmacol 89:1–11

    Article  CAS  Google Scholar 

  136. Camerer E, Qazi AA, Duong DN, Cornelissen I, Advincula R, Coughlin SR (2004) Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood 104(2):397–401

    Article  CAS  PubMed  Google Scholar 

  137. Jain S, Russell S, Ware J (2009) Platelet glycoprotein VI facilitates experimental lung metastasis in syngenic mouse models. J Thromb Haemost 7(10):1713–1717

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Schober LJ, Khandoga AL, Dwivedi S, Penz SM, Maruyama T, Brandl R, Siess W (2011) The role of PGE(2) in human atherosclerotic plaque on platelet EP(3) and EP(4) receptor activation and platelet function in whole blood. J Thromb Thrombolysis 32(2):158–166

    Article  CAS  PubMed  Google Scholar 

  140. Singh J, Zeller W, Zhou N, Hategen G, Mishra R, Polozov A, Yu P, Onua E, Zhang J, Zembower D, Kiselyov A, Ramírez JL, Sigthorsson G (2009) Antagonists of the EP3 receptor for prostaglandin E2 are novel antiplatelet agents that do not prolong bleeding. ACS Chem Biol 4:115–126

    Article  CAS  PubMed  Google Scholar 

  141. Fox SC, May JA, Johnson A, Hermann D, Strieter D, Hartman D, Heptinstall S (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 

  142. Semple JW, Italiano JE Jr, Freedman J (2011) Platelets and the immune continuum. Nat Rev Immunol 11(4):264–274

    Article  CAS  PubMed  Google Scholar 

  143. Li C, Li J, Li Y, Lang S, Yougbare I, Zhu G, Chen P, Ni H (2012) Crosstalk between platelets and the immune system: old systems with new discoveries. Adv Hematol 2012:384685

    PubMed  PubMed Central  Google Scholar 

  144. Nieswandt B, Hafner M, Echtenacher B, Mannel DN (1999) Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 59(6):1295–1300

    CAS  PubMed  Google Scholar 

  145. Cognasse F, Nguyen KA, Damien P, McNicol A, Pozzetto B, Hamzeh-Cognasse H, Garraud O (2015) The inflammatory role of platelets via their TLRs and Siglec receptors. Front Immunol 2(6):83

    Google Scholar 

  146. Yeaman MR (2014) Platelets: at the nexus of antimicrobial defence. Nat Rev Microbiol 12(6):426–437

    Article  CAS  PubMed  Google Scholar 

  147. Langer HF, Choi EY, Zhou H, Schleicher R, Chung KJ, Tang Z, Göbel K, Bdeir K, Chatzigeorgiou A, Wong C, Bhatia S, Kruhlak MJ, Rose JW, Burns JB, Hill KE, Qu H, Zhang Y, Lehrmann E, Becker KG, Wang Y, Simon DI, Nieswandt B, Lambris JD, Li X, Meuth SG, Kubes P, Chavakis T (2012) Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis. Circ Res 110(9):1202–1210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (Grant PRIN 2010–2011, Protocol Number 2010FHH32M), and Associazione Italiana per la Ricerca sul Cancro (Grant IG-12111) (to P. Patrignani).

Author information

Author notes

  1. Annalisa Contursi and Angela Sacco contributed equally.

Authors and Affiliations

  1. Section of Cardiovascular and Pharmacological Sciences, Department of Neuroscience, Imaging and Clinical Science, and CeSI-MeT (Centro Scienze dell’ Invecchiamento e Medicina Traslazionale), “G. d’Annunzio” University, Via dei Vestini 31, 66100, Chieti, Italy

    Annalisa Contursi, Angela Sacco, Rosalia Grande, Melania Dovizio & Paola Patrignani

Authors
  1. Annalisa Contursi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angela Sacco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rosalia Grande
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Melania Dovizio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paola Patrignani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paola Patrignani.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Contursi, A., Sacco, A., Grande, R. et al. Platelets as crucial partners for tumor metastasis: from mechanistic aspects to pharmacological targeting. Cell. Mol. Life Sci. 74, 3491–3507 (2017). https://doi.org/10.1007/s00018-017-2536-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-017-2536-7

Keywords

Search

Navigation