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Contribution of platelets to tumour metastasis


Extensive experimental evidence shows that platelets support tumour metastasis. The activation of platelets and the coagulation system have a crucial role in the progression of cancer. Within the circulatory system, platelets guard tumour cells from immune elimination and promote their arrest at the endothelium, supporting the establishment of secondary lesions. These contributions of platelets to tumour cell survival and spread suggest platelets as a new avenue for therapy.

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Figure 1: Platelet biology.
Figure 2: Molecular coordination between platelets and tumour cells supports metastasis from the bloodstream.


  1. 1

    Khorana, A. A. & Connolly, G. C. Assessing risk of venous thromboembolism in the patient with cancer. J. Clin. Oncol. 27, 4839–4847 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Lyman, G. H. & Khorana, A. A. Cancer, clots and consensus: new understanding of an old problem. J. Clin. Oncol. 27, 4821–4826 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Khorana, A. A. & Fine, R. L. Pancreatic cancer and thromboembolic disease. Lancet Oncol. 5, 655–663 (2004).

    CAS  PubMed  Google Scholar 

  4. 4

    Lugassy, G., Falanga, A., Kakkar, A. & Rickles, F. Thrombosis and Cancer (Informa Health Care, London, 2004).

  5. 5

    Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nature Rev. Cancer 9, 239–252 (2009).

    CAS  Article  Google Scholar 

  6. 6

    Trousseau, A. in Clinique Medicale de l'Hotel-Dieu de Paris 2nd ed (ed. Bailliere, J. B. ) Vol. 3, 654–712 (Paris,1865).

  7. 7

    Khorana, A. A. Malignancy, thrombosis and Trousseau: the case for an eponym. J. Thromb. Haemost. 1, 2463–2465 (2003).

    CAS  PubMed  Google Scholar 

  8. 8

    Sierko, E. & Wojtukiewicz, M. Z. Inhibition of platelet function: does it offer a chance of better cancer progression control? Semin. Thromb. Hemost. 33, 712–721 (2007).

    CAS  PubMed  Google Scholar 

  9. 9

    Sierko, E. & Wojtukiewicz, M. Z. Platelets and angiogenesis in malignancy. Semin. Thromb. Hemost. 30, 95–108 (2004).

    CAS  Google Scholar 

  10. 10

    Prisco, D. et al. Platelet activation and platelet lipid composition in pulmonary cancer Prostaglandins Leukot. Essent. Fatty Acids 53, 65–68 (1995).

    CAS  PubMed  Google Scholar 

  11. 11

    Blann, A. D. et al. Increased soluble P-selectin in patients with haematological and breast cancer: a comparison with fibrinogen, plasminogen activator inhibitor and von Willebrand factor. Blood Coagul. Fibrinolysis 12, 43–50 (2001).

    CAS  PubMed  Google Scholar 

  12. 12

    Verheul, H. M. W. et al. Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas. Clin. Cancer Res. 6, 166–171 (2000).

    CAS  PubMed  Google Scholar 

  13. 13

    Erdemir, F. et al. Clinical significance of platelet count in patients with renal cell carcinoma. Urol. Int. 79, 111–116 (2007).

    PubMed  Google Scholar 

  14. 14

    Costantini, V., Zacharski, L. R., Moritz, T. E. & Edwards, R. L. The platelet count in carcinoma of the lung and colon. Thromb. Haemost. 64, 501–505 (1990).

    CAS  PubMed  Google Scholar 

  15. 15

    Ayhan, A. et al. The value of preoperative platelet count in the prediction of cervical involvement and poor prognostic variables in patients with endometrial carcinoma. Gynecol. Oncol. 103, 902–905 (2006).

    PubMed  Google Scholar 

  16. 16

    Taucher, S. et al. Impact of pretreatment thrombocytosis on survival in primary breast cancer. Thromb. Haemost. 89, 1098–1106 (2003).

    CAS  PubMed  Google Scholar 

  17. 17

    Brown, K. M., Domin, C., Aranha, G. V., Yong, S. & Shoup, M. Increased preoperative platelet count is associated with decreased survival after resection for adenocarcinoma of the pancreas. Am. J. Surg. 189, 278–282 (2005).

    PubMed  Google Scholar 

  18. 18

    Bensalah, K. et al. Prognostic value of thrombocytosis in renal cell carcinoma. J. Urol. 175, 859–863 (2006).

    PubMed  Google Scholar 

  19. 19

    Brockmann, M. A. et al. Preoperative thrombocytosis predicts poor survival in patients with glioblastoma. Neuro-Oncology 9, 335–342 (2007).

    PubMed  PubMed Central  Google Scholar 

  20. 20

    Kaushansky, K. Historical review: megakaryopoiesis and thrombopoiesis. Blood 111, 981–986 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Ruggeri, Z. M. & Mendolicchio, G. L. Adhesion mechanisms in platelet function. Circ. Res. 100, 1673–1685 (2007).

    CAS  PubMed  Google Scholar 

  22. 22

    Davi, G. & Patrono, C. Platelet activation and atherothrombosis. N. Engl. J. Med. 357, 2482–2494 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Kakkar, A. K., Deruvo, N., Chinswangwatanakul, V., Tebbutt, S. & Williamson, R. C. N. Extrinsic-pathway activation in cancer with high factor VIIA and tissue factor. Lancet 346, 1004–1005 (1995).

    CAS  PubMed  Google Scholar 

  24. 24

    Mueller, B. M., Reisfeld, R. A., Edgington, T. S. & Ruf, W. Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. Proc. Natl Acad. Sci. USA 89, 11832–11836 (1992).

    CAS  PubMed  Google Scholar 

  25. 25

    Ruf, W. & Mueller, B. M. Thrombin generation and the pathogenesis of cancer. Semin. Thromb. Hemost. 32, 061, 068 (2006).

    CAS  Google Scholar 

  26. 26

    Esumi, N., Fan, D. & Fidler, I. J. Inhibition of murine melanoma experimental metastasis by recombinant desulfatohirudin, a highly specific thrombin inhibitor. Cancer Res. 51, 4549–4556 (1991).

    CAS  PubMed  Google Scholar 

  27. 27

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

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Hu, L., Lee, M., Campbell, W., Perez-Soler, R. & Karpatkin, S. Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood 104, 2746–2751 (2004).

    CAS  PubMed  Google Scholar 

  29. 29

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

    CAS  PubMed  Google Scholar 

  30. 30

    Ruf, W. Tissue factor and PAR signaling in tumor progression. Thromb. Res. 120, S7–S12 (2007).

    PubMed  Google Scholar 

  31. 31

    Ruf, W., Yokota, N. & Schaffner, F. Tissue factor in cancer progression and angiogenesis. Thromb. Res. 125, S36–S38 (2010).

    PubMed  Google Scholar 

  32. 32

    Gupta, G. P. & Massague, J. Cancer metastasis: Building a framework. Cell 127, 679–695 (2006).

    CAS  PubMed  Google Scholar 

  33. 33

    Nguyen, D. X., Bos, P. D. & Massague, J. Metastasis: from dissemination to organ-specific colonization. Nature Rev. Cancer 9, 274–284 (2009).

    CAS  Google Scholar 

  34. 34

    Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nature Rev. Cancer 9, 285–293 (2009).

    CAS  Google Scholar 

  35. 35

    Steeg, P. S. Tumor metastasis: mechanistic insights and clinical challenges. Nature Med. 12, 895–904 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer 2, 563–572 (2002).

    CAS  Google Scholar 

  37. 37

    Honn, K. V., Tang, D. G. & Chen, Y. Q. Platelets and cancer metastasis-more than an epiphenomenon. Semin. Thromb. Hemost. 18, 392–415 (1992).

    CAS  PubMed  Google Scholar 

  38. 38

    Mehta, P. Potential role of platelets in the pathogenesis of tumor-metastasis. Blood 63, 55–63 (1984).

    CAS  PubMed  Google Scholar 

  39. 39

    Jurasz, P., Alonso-Escolano, D. & Radomski, M. W. Platelet-cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. Br. J. Pharmacol. 143, 819–826 (2004).

    CAS  Google Scholar 

  40. 40

    Erpenbeck, L. & Schon, M. P. Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood 115, 3427–3436 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Folkman, J. et al. Tumor angiogenesis-therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

    CAS  Google Scholar 

  42. 42

    Mohle, R., Green, D., Moore, M., Nachman, R. & Rafii, S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc. Natl Acad. Sci. USA 94, 663–668 (1997).

    CAS  Google Scholar 

  43. 43

    Pinedo, H. M., Verheul, H. M. W., D'Amato, R. J. & Folkman, J. Involvement of platelets in tumour angiogenesis? The Lancet 352, 1775–1777 (1998).

    CAS  Google Scholar 

  44. 44

    Coppinger, J. A. et al. Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 103, 2096–2104 (2004).

    CAS  PubMed  Google Scholar 

  45. 45

    Smyth, S. S. et al. Platelet functions beyond hemostasis. J. Thromb. Haemost. 7, 1759–1766 (2009).

    CAS  PubMed  Google Scholar 

  46. 46

    Brock, T. A., Dvorak, H. F. & Senger, D. R. Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells. Am. J. Pathol. 138, 213–221 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Jin, D. K. et al. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nature Med. 12, 557–567 (2006).

    CAS  Google Scholar 

  48. 48

    Ma, L. et al. Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. Proc. Natl Acad. Sci. USA 102, 216–220 (2005).

    CAS  PubMed  Google Scholar 

  49. 49

    Italiano, J. E. Jr et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet α granules and differentially released. Blood 111, 1227–1233 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Boucharaba, A. et al. Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J. Clin. Invest. 114, 1714–1725 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Kim, Y. J., Borsig, L., Varki, N. M. & Varki, A. P-selectin deficiency attenuates tumor growth and metastasis. Proc. Natl Acad. Sci. USA 95, 9325–9330 (1998).

    CAS  PubMed  Google Scholar 

  52. 52

    Zaslavsky, A. et al. Platelet-derived thrombospondin-1 is a critical negative regulator and potential biomarker of angiogenesis. Blood 115, 4605–4613 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Palumbo, J. S. et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 105, 178–185 (2005).

    CAS  PubMed  Google Scholar 

  54. 54

    Palumbo, J. S. et al. Spontaneous hematogenous and lymphatic metastasis, but not primary tumor growth or angiogenesis, is diminished in fibrinogen-deficient mice. Cancer Res. 62, 6966–6972 (2002).

    CAS  PubMed  Google Scholar 

  55. 55

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

    CAS  PubMed  Google Scholar 

  56. 56

    Ho-Tin-Noe, B., Goerge, T., Cifuni, S. M., Duerschmied, D. & Wagner, D. D. Platelet granule secretion continuously prevents intratumor hemorrhage. Cancer Res. 68, 6851–6858 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Ho-Tin-Noe, B. et al. Innate immune cells induce hemorrhage in tumors during thrombocytopenia. Am. J. Pathol. 175, 1699–1708 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Ho-Tin-Noe, B., Goerge, T. & Wagner, D. D. Platelets: guardians of tumor vasculature. Cancer Res. 69, 5623–5626 (2009).

    CAS  PubMed  Google Scholar 

  59. 59

    Kisucka, J. et al. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage. Proc. Natl Acad. Sci. USA 103, 855–860 (2006).

    CAS  PubMed  Google Scholar 

  60. 60

    Manegold, P. C., Hutter, J., Pahernik, S. A., Messmer, K. & Dellian, M. Platelet-endothelial interaction in tumor angiogenesis and microcirculation. Blood 101, 1970–1976 (2003).

    CAS  PubMed  Google Scholar 

  61. 61

    Gasic, G. J., Gasic, T. B. & Stewart, C. C. Antimetastatic effects associated with platelet reduction. Proc. Natl Acad. Sci. USA 61, 46–52 (1968).

    CAS  PubMed  Google Scholar 

  62. 62

    Camerer, E. et al. Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood 104, 397–401 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

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

    CAS  Google Scholar 

  64. 64

    Sambrano, G. R., Weiss, E. J., Zheng, Y.-W., Huang, W. & Coughlin, S. R. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature 413, 74–78 (2001).

    CAS  PubMed  Google Scholar 

  65. 65

    Palumbo, J. S. et al. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood 96, 3302–3309 (2000).

    CAS  PubMed  Google Scholar 

  66. 66

    Versteeg, H. H. et al. Protease-activated receptor (PAR) 2, but not PAR1, signaling promotes the development of mammary adenocarcinoma in polyoma middle T mice. Cancer Res. 68, 7219–7227 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Hu, L., Roth, J. M., Brooks, P., Ibrahim, S. & Karpatkin, S. Twist is required for thrombin-induced tumor angiogenesis and growth. Cancer Res. 68, 4296–4302 (2008).

    CAS  PubMed  Google Scholar 

  68. 68

    Jones, D. S., Wallace, A. C. & Fraser, E. E. Sequence of events in experimental metastases of walker 256 tumor-light, immunofluorescent, and electron microscopic observations. J. Natl. Cancer Inst. 46, 493-& (1971).

    Google Scholar 

  69. 69

    Crissman, J. D., Hatfield, J., Schaldenbrand, M., Sloane, B. F. & Honn, K. V. Arrest and extravasation of B16 amelanotic melanoma in murine lungs. A light and electron microscopic study. Lab. Invest. 53, 470–478 (1985).

    CAS  PubMed  Google Scholar 

  70. 70

    Sindelar, W. F., Tralka, T. S. & Ketcham, A. S. Electron microscopic observations on formation of pulmonary metastases. J. Surg. Res. 18, 137–161 (1975).

    CAS  PubMed  Google Scholar 

  71. 71

    Borsig, L. et al. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc. Natl Acad. Sci. USA 98, 3352–3357 (2001).

    CAS  PubMed  Google Scholar 

  72. 72

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

    CAS  PubMed  Google Scholar 

  73. 73

    Malik, G. et al. Plasma fibronectin promotes lung metastasis by contributions to fibrin clots and tumor cell invasion. Cancer Res. 70, 4327–4334 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Palumbo, J. S. Mechanisms linking tumor cell-associated procoagulant function to tumor dissemination. Semin. Thromb. Hemost. 34, 154–160 (2008).

    CAS  PubMed  Google Scholar 

  75. 75

    Palumbo, J. S. et al. Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and-independent mechanisms. Blood 110, 133–141 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Wenzel, J., Zeisig, R. & Fichtner, I. Inhibition of metastasis in a murine 4T1 breast cancer model by liposomes preventing tumor cell-platelet interactions. Clin. Exp. Metastasis 27, 25–34 (2010).

    CAS  PubMed  Google Scholar 

  77. 77

    Offermanns, S., Toombs, C. F., Hu, Y.-H. & Simon, M. I. Defective platelet activation in G-α-q-deficient mice. Nature 389, 183–186 (1997).

    CAS  PubMed  Google Scholar 

  78. 78

    Palumbo, J. S. & Degen, J. L. Mechanisms linking tumor cell-associated procoagulant function to tumor metastasis. Thromb. Res. 120, S22–S28 (2007).

    Google Scholar 

  79. 79

    Kopp, H. G., Placke, T. & Salih, H. R. Platelet-derived transforming growth factor-β down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Res. 69, 7775–7783 (2009).

    CAS  PubMed  Google Scholar 

  80. 80

    Im, J. H. et al. Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res. 64, 8613–8619 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Läubli, H. & Borsig, L. Selectins promote tumor metastasis. Semin. Cancer Biol. 20, 169–177 (2010).

    PubMed  Google Scholar 

  82. 82

    Konstantopoulos, K. & Thomas, S. N. Cancer cells in transit: the vascular interactions of tumor cells. Annu. Rev. Biomed. Eng. 11, 177–202 (2009).

    CAS  PubMed  Google Scholar 

  83. 83

    Kim, Y. J., Borsig, L., Han, H. L., Varki, N. M. & Varki, A. Distinct selectin ligands on colon carcinoma mucins can mediate pathological interactions among platelets, leukocytes, and endothelium. Am. J. Pathol. 155, 461–472 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Ludwig, R. J. et al. Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis. Cancer Res. 64, 2743–2750 (2004).

    CAS  PubMed  Google Scholar 

  85. 85

    Mousa, S. A. & Petersen, L. J. Anti-cancer properties of low-molecular-weight heparin: preclinical evidence. Thromb. Haemost. 102, 258–267 (2009).

    CAS  PubMed  Google Scholar 

  86. 86

    Varki, A. P., Varki, N. M. & Borsig, L. Selectins, heparins, and cancer: rationale for clinical trials. Blood 112, 1348–1348 (2008).

    Google Scholar 

  87. 87

    Borsig, L., Wong, R., Hynes, R. O., Varki, N. M. & Varki, A. Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc. Natl Acad. Sci. USA 99, 2193–2198 (2002).

    CAS  PubMed  Google Scholar 

  88. 88

    Laubli, H., Spanaus, K. S. & Borsig, L. Selectin-mediated activation of endothelial cells induces expression of CCL5 and promotes metastasis through recruitment of monocytes. Blood 114, 4583–4591 (2009).

    CAS  PubMed  Google Scholar 

  89. 89

    Alves, C. S., Burdick, M. M., Thomas, S. N., Pawar, P. & Konstantopoulos, K. The dual role of CD44 as a functional P-selectin ligand and fibrin receptor in colon carcinoma cell adhesion. Am. J. Physiol. Cell Physiol. 294, C907–C916 (2008).

    CAS  PubMed  Google Scholar 

  90. 90

    McCarty, O. J. T., Mousa, S. A., Bray, P. F. & Konstantopoulos, K. Immobilized platelets support human colon carcinoma cell tethering, rolling, and firm adhesion under dynamic flow conditions. Blood 96, 1789–1797 (2000).

    CAS  PubMed  Google Scholar 

  91. 91

    Shattil, S. J., Kim, C. & Ginsberg, M. H. The final steps of integrin activation: the end game. Nature Rev. Mol. Cell Biol. 11, 288–300 (2010).

    CAS  Google Scholar 

  92. 92

    Felding-Habermann, B., Habermann, R., Saldivar, E. & Ruggeri, Z. M. Role of β3 integrins in melanoma cell adhesion to activated platelets under flow. J. Biol. Chem. 271, 5892–5900 (1996).

    CAS  Google Scholar 

  93. 93

    Amirkhosravi, A. et al. Inhibition of tumor cell-induced platelet aggregation and lung metastasis by the oral GpIIb/IIIa antagonist XV454. Thromb. Haemost. 90, 549–554 (2003).

    CAS  PubMed  Google Scholar 

  94. 94

    Desgrosellier, J. S. & Cheresh, D. A. Integrins in cancer: biological implications and therapeutic opportunities. Nature Rev. Cancer 10, 9–22 (2010).

    CAS  Google Scholar 

  95. 95

    Bakewell, S. J. et al. Platelet and osteoclast β3 integrins are critical for bone metastasis. Proc. Natl Acad. Sci. USA 100, 14205–14210 (2003).

    CAS  Google Scholar 

  96. 96

    Gupta, G. P. & Massague, J. Platelets and metastasis revisited: a novel fatty link. J. Clin. Invest. 114, 1691–1693 (2004).

    CAS  Google Scholar 

  97. 97

    Arnaout, M. A., Mahalingam, B. & Xiong, J.-P. Integrin structure, allostery, and bidirectional signaling. Annu. Rev. Cell Dev. Biol. 21, 381–410 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Rose, D. M., Alon, R. & Ginsberg, M. H. Integrin modulation and signaling in leukocyte adhesion and migration. Immunol. Rev. 218, 126–134 (2007).

    CAS  PubMed  Google Scholar 

  99. 99

    Alcaide, P., Auerbach, S. & Luscinskas, F. W. Neutrophil recruitment under shear flow: it's all about endothelial cell rings and gaps. Microcirculation 16, 43–57 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Zarbock, A. & Ley, K. Mechanisms and consequences of neutrophil interaction with the endothelium. Am. J. Pathol. 172, 1–7 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Barthel, S. R., Johansson, M. W., McNamee, D. M. & Mosher, D. F. Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma. J. Leukoc. Biol. 83, 1–12 (2008).

    CAS  PubMed  Google Scholar 

  102. 102

    Hyduk, S. J. & Cybulsky, M. I. Role of α4β1 integrins in chemokine-induced monocyte arrest under conditions of shear stress. Microcirculation 16, 17–30 (2009).

    CAS  PubMed  Google Scholar 

  103. 103

    Felding-Habermann, B. et al. Integrin activation controls metastasis in human breast cancer. Proc. Natl Acad. Sci. USA 98, 1853–1858 (2001).

    CAS  PubMed  Google Scholar 

  104. 104

    Rolli, M., Fransvea, E., Pilch, J., Saven, A. & Felding-Habermann, B. Activated integrin αvβ3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 9482–9487 (2003).

    CAS  PubMed  Google Scholar 

  105. 105

    Felding-Habermann, B. Targeting tumor cell-platelet interaction in breast cancer metastasis. Pathophysiol. Haemost. Thromb. 33, 56–58 (2003).

    PubMed  Google Scholar 

  106. 106

    Deryugina, E. & Quigley, J. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25, 9–34 (2006).

    CAS  PubMed  Google Scholar 

  107. 107

    Lorger, M., Krueger, J. S., O'Neal, M., Staflin, K. & Felding-Habermann, B. Activation of tumor cell integrin αvβ3 controls angiogenesis and metastatic growth in the brain. Proc. Natl Acad. Sci. USA 106, 10666–10671 (2009).

    CAS  Google Scholar 

  108. 108

    Felding-Habermann, B. et al. Combinatorial antibody libraries from cancer patients yield ligand-mimetic Arg-Gly-Asp-containing immunoglobulins that inhibit breast cancer metastasis. Proc. Natl Acad. Sci. USA 101, 17210–17215 (2004).

    CAS  PubMed  Google Scholar 

  109. 109

    Staflin, K. et al. Targeting activated integrin αvβ3 with patient-derived antibodies impacts late-stage multiorgan metastasis. Clin. Exp. Metastasis 27, 217–231 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Taverna, D., Crowley, D., Connolly, M., Bronson, R. T. & Hynes, R. O. A direct test of potential roles for β3 and β5 integrins in growth and metastasis of murine mammary carcinomas. Cancer Res. 65, 10324–10329 (2005).

    CAS  PubMed  Google Scholar 

  111. 111

    Morimoto, K. et al. Interaction of cancer cells with platelets mediated by Necl-5/poliovirus receptor enhances cancer cell metastasis to the lungs. Oncogene 27, 264–273 (2007).

    PubMed  Google Scholar 

  112. 112

    Jain, S. et al. Platelet glycoprotein Ibα supports experimental lung metastasis. Proc. Natl Acad. Sci. USA 104, 9024–9028 (2007).

    CAS  PubMed  Google Scholar 

  113. 113

    Kitagawa, H. et al. Involvement of platelet membrane glycoprotein Ib and glycoprotein IIb/IIIa complex in thrombin-dependent and -independent platelet aggregations induced by tumor cells. Cancer Res. 49, 537–541 (1989).

    CAS  PubMed  Google Scholar 

  114. 114

    Erpenbeck, L., Nieswandt, B., Schon, M., Pozgajova, M. & Schon, M. P. Inhibition of platelet GPIbα and promotion of melanoma metastasis. J. Invest. Dermatol. 130, 576–586 (2009).

    PubMed  Google Scholar 

  115. 115

    Terraube, V. et al. Increased metastatic potential of tumor cells in von Willebrand factor-deficient mice. J. Thromb. Haemost. 4, 519–526 (2006).

    CAS  PubMed  Google Scholar 

  116. 116

    Terraube, V., Marx, I. & Denis, C. V. Role of von Willebrand factor in tumor metastasis. Thromb. Res. 120, S64–S70 (2007).

    PubMed  Google Scholar 

  117. 117

    Marsolais, D. & Rosen, H. Chemical modulators of sphingosine 1 -phosphate receptors as barrier-oriented therapeutic molecules. Nature Rev. Drug Discov. 8, 297–307 (2009).

    CAS  Google Scholar 

  118. 118

    Yatomi, Y. et al. Sphingosine 1 -phosphate as a major bioactive lysophospholipid that is released from platelets and interacts with endothelial cells. Blood 96, 3431–3438 (2000).

    CAS  PubMed  Google Scholar 

  119. 119

    Schaphorst, K. L. et al. Role of sphingosine 1 -phosphate in the enhancement of endothelial barrier integrity by platelet-released products. Am. J. Physiol. Lung Cell. Mol. Physiol. 285, L258–L267 (2003).

    CAS  PubMed  Google Scholar 

  120. 120

    Yin, F. & Watsky, M. A. LPA and S1P increase corneal epithelial and endothelial cell transcellular resistance. Invest. Ophthalmol. Vis. Sci. 46, 1927–1933 (2005).

    CAS  PubMed  Google Scholar 

  121. 121

    Sarker, M. H., Hu, D. E. & Fraser, P. A. Regulation of cerebromicrovascular permeability by lysophosphatidic acid. Microcirculation 17, 39–46 (2010).

    CAS  PubMed  Google Scholar 

  122. 122

    Côté, F., Fligny, C., Fromes, Y., Mallet, J. & Vodjdani, G. Recent advances in understanding serotonin regulation of cardiovascular function. Trend in Mol. Med. 10, 232–238 (2004).

    Google Scholar 

  123. 123

    Skolnik, G., Bagge, U., Dhlstrom, A. & Ahlman, H. The importance of 5-HT for tumor cell lodgement in the liver. Int. J. Cancer 33, 519–523 (1984).

    CAS  PubMed  Google Scholar 

  124. 124

    Skolnik, G., Bagge, U., Blomqvist, G., Djarv, L. & Ahlman, H. The role of calcium channels and serotonin (5-HT2) receptors for tumour cell lodegment in the liver. Clin. Exp. Metastasis 7, 169–174 (1989).

    CAS  PubMed  Google Scholar 

  125. 125

    Kuna, P. et al. RANTES, a monocyte and T lymphocyte chemotactic cytokine releases histamine from human basophils. J. Immunol. 149, 636–642 (1992).

    CAS  Google Scholar 

  126. 126

    Lyman, G. H. et al. American society of clinical oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J. Clin. Oncol. 25, 5490–5505 (2007).

    CAS  PubMed  Google Scholar 

  127. 127

    Varki, A. Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood 110, 1723–1729 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Elwood, P. C., Gallagher, A. M., Duthie, G. G., Mur, L. A. J. & Morgan, G. Aspirin, salicylates, and cancer. The Lancet 373, 1301–1309 (2009).

    CAS  Google Scholar 

  129. 129

    Mackman, N. Triggers, targets and treatments for thrombosis. Nature 451, 914–918 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Verheul, H. M. W. et al. Platelets take up the monoclonal antibody bevacizumab. Clin. Cancer Res. 13, 5341–5347 (2007).

    CAS  PubMed  Google Scholar 

  131. 131

    Kanter, J., Khan, S. Y., Kelher, M., Gore, L. & Silliman, C. C. Oncogenic and angiogenic growth factors accumulate during routine storage of apheresis platelet concentrates. Clin. Cancer Res. 14, 3942–3947 (2008).

    CAS  PubMed  Google Scholar 

  132. 132

    Foss, B. & Bruserud, O. Platelet functions and clinical effects in acute myelogenous leukemia. Thromb. Haemost. 99, 27–37 (2008).

    CAS  PubMed  Google Scholar 

  133. 133

    Cervi, D. et al. Platelet-associated PF-4 as a biomarker of early tumor growth. Blood 111, 1201–1207 (2008).

    CAS  Google Scholar 

  134. 134

    Klement, G. L. et al. Platelets actively sequester angiogenesis regulators. Blood 113, 2835–2842 (2009).

    CAS  PubMed  Google Scholar 

  135. 135

    Borsig, L. The role of platelet activation in tumor metastasis. Expert Rev. Anticancer Ther. 8, 1247–1255 (2008).

    CAS  PubMed  Google Scholar 

  136. 136

    Fang, J. et al. Therapeutic expression of the platelet-specific integrin, αIIbβ3, in a murine model for Glanzmann thrombasthenia. Blood 106, 2671–2679 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Freyssinet, J.-M. & Toti, F. Formation of procoagulant microparticles and properties. Thromb. Res. 125, S46–S48 (2010).

    CAS  PubMed  Google Scholar 

  138. 138

    Muralidharan-Chari, V., Clancy, J. W., Sedgwick, A. & D'Souza-Schorey, C. Microvesicles: mediators of extracellular communication during cancer progression. J. Cell Sci. 123, 1603–1611 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Castellana, D., Toti, F. & Freyssinet, J. M. Membrane microvesicles: macromessengers in cancer disease and progression. Thromb. Res. 125, S84–S88 (2010).

    PubMed  Google Scholar 

  140. 140

    Baj-Krzyworzeka, M. et al. Platelet-derived microparticles stimulate proliferation, survival, adhesion, and chemotaxis of hematopoietic cells. Exp. Hematol. 30, 450–459 (2002).

    CAS  PubMed  Google Scholar 

  141. 141

    Janowska-Wieczorek, A., Marquez-Curtis, L. A., Wysoczynski, M. & Ratajczak, M. Z. Enhancing effect of platelet-derived microvesicles on the invasive potential of breast cancer cells. Transfusion (Paris). 46, 1199–1209 (2006).

    Google Scholar 

  142. 142

    Janowska-Wieczorek, A. et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int. J. Cancer 113, 752–760 (2005).

    CAS  PubMed  Google Scholar 

  143. 143

    Dashevsky, O., Varon, D. & Brill, A. Platelet-derived microparticles promote invasiveness of prostate cancer cells via upregulation of MMP-2 production. Int. J. Cancer 124, 1773–1777 (2009).

    CAS  PubMed  Google Scholar 

  144. 144

    Kalinkovich, A. et al. Functional CXCR4-expressing microparticles and SDF-1 correlate with circulating acute myelogenous leukemia cells. Cancer Res. 66, 11013–11020 (2006).

    CAS  PubMed  Google Scholar 

  145. 145

    Kim, H. K. et al. Elevated levels of circulating platelet microparticles, VEGF, IL-6 and RANTES in patients with gastric cancer: possible role of a metastasis predictor. Eur. J. Cancer 39, 184–191 (2003).

    CAS  PubMed  Google Scholar 

  146. 146

    Helley, D. et al. Platelet microparticles: a potential predictive factor of survival in hormone-refractory prostate cancer patients treated with docetaxel-based chemotherapy. Eur. Urol. 56, 479–484 (2009).

    CAS  PubMed  Google Scholar 

  147. 147

    Hron, G. et al. Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb. Haemost. 97, 119–123 (2007).

    CAS  PubMed  Google Scholar 

  148. 148

    Tesselaar, M. E. et al. Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J. Thromb. Haemost. 5, 520–527 (2007).

    CAS  PubMed  Google Scholar 

  149. 149

    Toth, B. et al. Platelet-derived microparticles and coagulation activation in breast cancer patients. Thromb. Haemost. 100, 663–669 (2008).

    CAS  PubMed  Google Scholar 

  150. 150

    Thomas, G. M. et al. Cancer cell-derived microparticles bearing P-selectin glycoprotein ligand 1 accelerate thrombus formation in vivo. J. Exp. Med. 206, 1913–1927 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Tilley, R. E., Holscher, T., Belani, R., Nieva, J. & Mackman, N. Tissue factor activity is increased in a combined platelet and microparticle sample from cancer patients. Thromb. Res. 122, 604–609 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Nachman, R. L. & Rafii, S. Platelets, petechiae, and preservation of the vascular wall. N. Engl. J. Med. 359, 1261–1270 (2008).

    CAS  Google Scholar 

  153. 153

    Von Hundelshausen, P. & Weber, C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ. Res. 100, 27–40 (2007).

    CAS  PubMed  Google Scholar 

  154. 154

    Popivanova, B. K. et al. Blockade of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice. Cancer Res. 69, 7884–7892 (2009).

    CAS  PubMed  Google Scholar 

  155. 155

    Jung, D.-W. et al. Tumor-stromal crosstalk in invasion of oral squamous cell carcinoma: a pivotal role of CCL7. Int. J. Cancer 127, 332–344 (2010).

    CAS  PubMed  Google Scholar 

  156. 156

    Keeley, E. C., Mehrad, B., Strieter, R. M., George, F. V. W. & George, K. in Adv. Cancer Res. 91–111 (Academic Press, 2010).

  157. 157

    Bajou, K. et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nature Med. 4, 923–928 (1998).

    CAS  PubMed  Google Scholar 

  158. 158

    Geiger, T. R. & Peeper, D. S. Critical role for TrkB kinase function in anoikis suppression, tumorigenesis, and metastasis. Cancer Res. 67, 6221–6229 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Bronckaers, A., Gago, F., Balzarini, J. & Liekens, S. The dual role of thymidine phosphorylase in cancer development and chemotherapy. Med. Res. Rev. 29, 903–953 (2009).

    CAS  PubMed  Google Scholar 

  160. 160

    Ikushima, H. & Miyazono, K. TGFβ signalling: a complex web in cancer progression. Nature Rev. Cancer 10, 415–424 (2010).

    CAS  Google Scholar 

  161. 161

    Medina, V. A. & Rivera, E. S. Histamine receptors and cancer pharmacology. Br. J. Pharmacol. 161, 755–767 (2010).

    CAS  Google Scholar 

  162. 162

    Falcon, B. L. et al. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am. J. Pathol. 175, 2159–2170 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Ho, M.-Y. et al. Nucleotide-binding domain of phosphoglycerate kinase 1 reduces tumor growth by suppressing COX-2 expression. Cancer Science 101, 2411–2416 (2010).

    CAS  PubMed  Google Scholar 

  164. 164

    Melnikova, V. & Bar-Eli, M. Inflammation and melanoma growth and metastasis: the role of platelet-activating factor (PAF) and its receptor. Cancer Metastasis Rev. 26, 359–371 (2007).

    CAS  PubMed  Google Scholar 

  165. 165

    Visentin, B. et al. Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell 9, 225–238 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    David, M. et al. Cancer cell expression of autotaxin controls bone metastasis formation in mouse through lysophosphatidic acid-dependent activation of osteoclasts. PLoS ONE 5, e9741 (2010).

    PubMed  PubMed Central  Google Scholar 

  167. 167

    Amirkhosravi, A. et al. The role of tissue factor pathway inhibitor in tumor growth and metastasis. Semin. Thromb. Hemost. 33, 643–652 (2007).

    CAS  PubMed  Google Scholar 

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B.F.H. is supported by grants from the US National Institutes of Health (NIH) (CA 112287), the California Breast Cancer Research Program (12NB0176 and 13NB0180) and the US Department of Defense (W81XWH-08-1-0468). L.J.G. is supported by a trainee scholarship from NIH grant 5TL1RR025772-03.

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Blood perfusion model

Parallel plate flow chamber system in which adhesive interactions between blood-borne tumour cells, blood cells, platelets and endothelial cells are monitored and measured by video microscopy.

Disseminated intravascular coagulation

Pathological activation of coagulation (blood clotting) mechanisms that leads to the formation of small blood clots in blood vessels throughout the body.

Endothelial retraction

Disruption of adherens junctions of endothelial cells creates gaps in the endothelial monolayer and increases vascular permeability while exposing the matrix proteins of the basement membrane.


Carbohydrate-linked lipids and proteins, which include receptors and ligands that function as cell adhesion molecules.

Migratory thrombophlebitis

Malignancy-associated hypercoagulable state leading to spontaneous platelet-rich clots in veins anywhere in the body that dynamically form, resolve and reappear.

Paraneoplastic disease

Disease induced as a result of tumour burden; generally caused by the release of tumour-derived hormones, peptides or cytokines, or by the misguided destruction of normal tissue by immune cells targeted against malignant cells.

Pulmonary embolism

Blockage of the main artery of the lung or one of its branches by a platelet-rich clot that originated in the venous circulation and dislodged from where it initially formed.

Shear stress

The velocity of flowing blood is highest in the centre of vessels and decreases towards the vessel wall, resulting in differential flow that generates a shearing force.

Thromboembolic disease

Condition caused by travelling blood clots or emboli that occlude blood vessels; commonly manifesting as deep vein thrombosis or pulmonary embolism in cancer patients.

Weibel–Palade bodies

Secretory granules of endothelial cells that particularly store and secrete multimerized von Willebrand factor, and which translocate P-selectin to the membrane surface on cell activation.

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

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