Skip to main content

Advertisement

SpringerLink
Log in

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

  • NON-THEMATIC REVIEW
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

The association between blood coagulation and cancer development is well recognized. Thrombin, the pleiotropic enzyme best known for its contribution to fibrin formation and platelet aggregation during vascular hemostasis, may also trigger cellular events through protease-activated receptors, PAR-1 and PAR-4, leading to cancer progression. Our pioneering findings provided evidence that thrombin contributes to cancer metastasis by increasing adhesive potential of malignant cells. However, there is evidence that thrombin regulates every step of cancer dissemination: (1) cancer cell invasion, detachment from primary tumor, migration; (2) entering the blood vessel; (3) surviving in vasculature; (4) extravasation; (5) implantation in host organs. Recent studies have provided new molecular data about thrombin generation in cancer patients and the mechanisms by which thrombin contributes to transendothelial migration, platelet/tumor cell interactions, angiogenesis, and other processes. Though a great deal is known regarding the role of thrombin in cancer dissemination, there are new data for multiple thrombin-mediated events that justify devoting focus to this topic with a comprehensive approach.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Konstantopoulos, K., & Thomas, S. N. (2009). Cancer cells in transit: the vascular interactions of tumor cells. Annual Review of Biomedical Engineering, 11, 177–202.

    Article  CAS  PubMed  Google Scholar 

  2. Tsopanoglou, N. E., & Maragoudakis, M. E. (2009). Thrombin’s central role in angiogenesis and pathophysiological processes. European Cytokine Network, 20(4), 171–179.

    CAS  PubMed  Google Scholar 

  3. Wojtukiewicz, M. Z., Hempel, D., Sierko, E., Tucker, S. C., & Honn, K. V. (2015). Protease-activated receptors (PARs)—biology and role in cancer invasion and metastasis. Cancer and Metastasis Reviews, 34(4), 775–796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wojtukiewicz, M.Z., Ciarelli, J.J., Walz, D.A., Honn, K.V. (1990). Thrombin enhances cancer cell expression of an integrin receptor and increases adhesion. 81st Annual Meeting of the American Association for Cancer Research, Washington, Proceedings of AACR, 31:Abstract 476.

  5. Wojtukiewicz, M.Z., Ciarelli, J.J., Snyder, D.A., Nelson, K.K., Walz, D.A., Honn, K.V. (1990). Increased tumor cell adhesiveness and experimental metastasis following exposure to alpha-thrombin, its precursor and analogues. American Cancer Society Michigan Division Inc., 1990 Cancer Research Conference, Ypsilanti, MI, USA, Poster 22.

  6. Wojtukiewicz, M.Z., Ciarelli, J.J., Snyder, D., Nelson, K.K., Walz, D.A., Honn, K.V. (1990). Thrombin increases tumor cell adhesiveness via a non-proteolytic pathway. First Regional Meeting of the American Society for Cell Biology, Chicago, IL, USA, 1990, Abstract 91.

  7. 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, 233–245.

    Article  CAS  PubMed  Google Scholar 

  8. Wojtukiewicz, M. Z., Tang, D. G., Ciarelli, J. J., Nelson, K. K., Walz, D. A., Diglio, C. A., et al. (1993). Thrombin increases the metastatic potential of tumor cells. International Journal of Cancer, 54, 793–806.

    Article  CAS  PubMed  Google Scholar 

  9. Pereira, L., Mariadason, J. M., Hannan, R. D., & Dhillon, A. S. (2015). Implications of epithelial-mesenchymal plasticity for heterogeneity in colorectal cancer. Frontiers in Oncology. doi:10.3389/fonc.2015.00013.

    PubMed  PubMed Central  Google Scholar 

  10. Zhang, T., Ma, Z., Wang, R., Wang, Y., Wang, S., Cheng, Z., et al. (2010). Thrombin facilitates invasion of ovarian cancer along peritoneum by inducing monocyte differentiation toward tumor-associated macrophage-like cells. Cancer Immunology, Immunotherapy, 59(7), 1097–1108.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang, P., Feng, S., Liu, G., Wang, H., Zhu, H., Ren, Q., et al. (2016). Mutant B-Raf (V600E) promotes melanoma paracellular transmigration by inducing thrombin-mediated endothelial junction breakdown. Journal of Biological Chemistry, 291(5), 2087–2106.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Nierodzik, M. L., Chen, K., Takeshita, K., Li, J. J., Huang, Y. Q., Feng, X. S., et al. (1998). Protease-activated receptor 1 (PAR-1) is required and rate-limiting for thrombin-enhanced experimental pulmonary metastasis. Blood, 92, 3694–3700.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. 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 

  17. Reitter, E. M., Kaider, A., Ay, C., Quehenberger, P., Marosi, C., Zielinski, C., et al. (2015). Longitudinal analysis of hemostasis biomarkers in cancer patients during the anti-tumor treatment. Journal of Thrombosis and Haemostasis. doi:10.1111/jth.13218.

    PubMed  Google Scholar 

  18. 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 

  19. Hu, L., Lee, M., Campbell, W., Perez-Soler, R., & Karpatkin, S. (2004). Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood, 104(9), 2746–2751.

    Article  CAS  PubMed  Google Scholar 

  20. Guo, R. R., Liu, Y., Lu, W. L., Zhao, J. H., Wang, X. Q., Zhang, H., et al. (2008). A recombinant peptide, hirudin, potentiates the inhibitory effects of stealthy liposomal vinblastine on the growth and metastasis of melanoma. Biological and Pharmaceutical Bulletin, 31(4), 696–702.

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. Queiroz, K. C., Shi, K., Duitman, J., Aberson, H. L., Wilmink, J. W., van Noesel, C. J., et al. (2014). Protease-activated receptor-1 drives pancreatic cancer progression and chemoresistance. International Journal of Cancer, 135(10), 2294–2304.

    Article  CAS  PubMed  Google Scholar 

  23. Yoon, H., Radulovic, M., Drucker, K. L., Wu, J., & Scarisbrick, I. A. (2015). The thrombin receptor is a critical extracellular switch controlling myelination. Glia, 63(5), 846–859.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bapat, A. A., Hostetter, G., Von Hoff, D. D., & Han, H. (2011). Perineural invasion and associated pain in pancreatic cancer. Nature Reviews Cancer, 11(10), 695–707.

    Article  CAS  PubMed  Google Scholar 

  25. Alexander, E. T., Minton, A. R., Hayes, C. S., Goss, A., Van Ryn, J., & Gilmour, S. K. (2015). Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis. Cancer Biology and Therapy, 16(12), 1802–1811.

    Article  CAS  PubMed  Google Scholar 

  26. Horowitz, N. A., Blevins, E. A., Miller, W. M., Perry, A. R., Talmage, K. E., Mullins, E. S., et al. (2011). Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain. Blood, 118(10), 2889–2895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. DeFeo, K., Hayes, C., Chernick, M., Ryn, J. V., & Gilmour, S. K. (2010). Use of dabigatran etexilate to reduce breast cancer progression. Cancer Biology and Therapy, 10, 1001–1008.

    Article  CAS  PubMed  Google Scholar 

  28. Nieman, M. T., LaRusch, G., Fang, C., Zhou, Y., & Schmaier, A. H. (2010). Oral thrombostatin FM19 inhibits prostate cancer. Thrombosis and Haemostasis, 104, 1044–1048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ratnoff, O. D., Ratnoff, O. D., & Forbes, C. D. (Eds.). (1996). The evolution of knowledge about hemostasis. Disorders of Hemostasis (3rd ed.). Philadelphia: WB Saunders Company.

    Google Scholar 

  30. Huntington, J. A. (2005). Molecular recognition mechanisms of thrombin. Journal of Thrombosis and Haemostasis, 3(8), 1861–1872.

    Article  CAS  PubMed  Google Scholar 

  31. Higgins, D. L., Lewis, S. D., & Shafer, J. A. (1983). Steady state kinetic parameters for the thrombin-catalyzed conversion of human fibrinogen to fibrin. Journal of Biological Chemistry, 258, 9276–9282.

    CAS  PubMed  Google Scholar 

  32. Boknäs, N., Faxälv, L., Sanchez Centellas, D., Wallstedt, M., Ramström, S., Grenegård, M., et al. (2014). Thrombin-induced platelet activation via PAR4, pivotal role for exosite II. Thrombosis and Haemostasis, 112(3), 558–565.

    Article  PubMed  CAS  Google Scholar 

  33. Vu, T. K., Hung, D. T., Wheaton, V. I., & Coughlin, S. R. (1991). Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell, 64(6), 10557–10568.

    Article  Google Scholar 

  34. Austin, K. M., Covic, L., & Kuliopulos, A. (2013). Matrix metalloproteases and PAR1 activation. Blood, 121(3), 431–439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  36. Ossovskaya, V. S., & Bunnett, N. W. (2004). Protease-activated receptors: contribution to physiology and disease. Physiological Reviews, 84(2), 579–621.

    Article  CAS  PubMed  Google Scholar 

  37. Lin, H., Liu, A. P., Smith, T. H., & Trejo, J. (2013). Cofactoring and dimerization of proteinase-activated receptors. Pharmacological Reviews, 65(4), 1198–1213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Junge, C. E., Lee, C. J., Hubbard, K. B., Zhang, Z., Olson, J. J., Hepler, J. R., et al. (2004). Protease-activated receptor-1 in human brain: localization and functional expression in astrocytes. Experimental Neurology, 188(1), 94–103.

    Article  CAS  PubMed  Google Scholar 

  39. Xie, Q., Bao, X., Chen, Z. H., Xu, Y., Keep, R. F., Muraszko, K. M., et al. (2016). Role of protease-activated receptor-1 in glioma growth. Acta Neurochirurgica Supplement, 121, 355–360.

    PubMed  Google Scholar 

  40. Li, S. M., Jiang, P., Xiang, Y., Wang, W. W., Zhu, Y. C., Feng, W. Y., et al. (2015). Protease-activated receptor (PAR)1, PAR2 and PAR4 expressions in esophageal squamous cell carcinoma. Dongwuxue Yanjiu, 35(5), 420–425.

    Google Scholar 

  41. Adams, G. N., Rosenfeldt, L., Frederick, M., Miller, W., Waltz, D., Kombrinck, K., et al. (2015). Colon cancer growth and dissemination relies upon thrombin, stromal PAR-1, and fibrinogen. Cancer Research, 75(19), 4235–4243.

    Article  CAS  PubMed  Google Scholar 

  42. 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, 11977–11984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Schulze, E. B., Hedley, B. D., Goodale, D., Postenka, C. O., Al-Katib, W., & Tuck, A. B. (2008). The thrombin inhibitor Argatroban reduces breast cancer malignancy and metastasis via osteopontin-dependent and osteopontin-independent mechanisms. Breast Cancer Research and Treatment, 112(2), 243–254.

    Article  CAS  PubMed  Google Scholar 

  44. Zain, J., Huang, Y. Q., Feng, X., Nierodzik, M. L., Li, J. J., & Karpatkin, S. (2000). Concentration-dependent dual effect of thrombin on impaired growth/apoptosis or mitogenesis in tumor cells. Blood, 95(10), 3133–3138.

    CAS  PubMed  Google Scholar 

  45. Wojtukiewicz, M. Z., Sierko, E., & Rak, J. (2004). Contribution of the hemostatic system to angiogenesis in cancer. Seminars in Thrombosis and Hemostasis, 30(1), 5–20.

    Article  CAS  PubMed  Google Scholar 

  46. van den Berg, Y. W., Osanto, S., Reitsma, P. H., & Versteeg, H. H. (2012). The relationship between tissue factor and cancer progression: insights from bench and bedside. Blood, 119(4), 924–932.

    Article  PubMed  CAS  Google Scholar 

  47. Schaffner, F., & Ruf, W. (2009). Tissue factor and PAR2 signaling in the tumor microenvironment. Arteriosclerosis, Thrombosis, and Vascular Biology, 29(12), 1999–2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lindahl, U., Peiler, G., Bozgwald, J., & Seljelid, R. (1989). A prothrominase complex of mouse peritoneal macrophages. Archives of Biochemistry and Biophysics, 273, 180–188.

    Article  CAS  PubMed  Google Scholar 

  49. Vrana, J. A., Stang, M. T., Grande, J. P., & Getz, M. J. (1996). Expression of tissue factor in tumor stroma correlates with progression to invasive human breast cancer: paracrine regulation by carcinoma cell-derived members of the transforming growth factor beta family. Cancer Research, 56(21), 5063–5070.

    CAS  PubMed  Google Scholar 

  50. Wojtukiewicz, M. Z., Zacharski, L. R., Ruciñska, M., Zimnoch, L., Jaromin, J., Rózañska-Kudelska, M., et al. (1999). Expression of tissue factor and tissue factor pathway inhibitor in situ in laryngeal carcinoma. Thrombosis and Haemostasis, 82(6), 1659–1662.

    CAS  PubMed  Google Scholar 

  51. Wojtukiewicz, M. Z., Sierko, E., Zacharski, L. R., Zimnoch, L., Kudryk, B., & Kisiel, W. (2003). Tissue factor-dependent coagulation activation and impaired fibrinolysis in situ in gastric cancer. Seminars in Thrombosis and Hemostasis, 29(3), 291–300.

    Article  CAS  PubMed  Google Scholar 

  52. Menter, D. G., Tucker, S. C., Kopetz, S., Sood, A. K., Crissman, J. D., & Honn, K. V. (2014). Platelets and cancer: a casual or causal relationship: revisited. Cancer Metastasis Reviews, 33(1), 231–269.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Young, A., Chapman, O., Connor, C., Poole, C., Rose, P., & Kakkar, A. K. (2012). Thrombosis and cancer. Nature Reviews. Clinical Oncology, 9(8), 437–449.

    Article  CAS  PubMed  Google Scholar 

  54. Thomas, G. M., Brill, A., Mezouar, S., Crescence, L., Gallant, M., Dubois, C., et al. (2015). Tissue factor expressed by circulating cancer cell-derived microparticles drastically increases the incidence of deep vein thrombosis in mice. Journal of Thrombosis and Haemostasis, 13(7), 1310–1319.

    Article  CAS  PubMed  Google Scholar 

  55. D’Asti, E., & Rak, J. (2016). Biological basis of personalized anticoagulation in cancer: oncogene and oncomir networks as putative regulators of coagulopathy. Thrombosis Research, 140(Suppl 1), 37–43.

    Article  CAS  Google Scholar 

  56. D’Andrea, M. R., Derian, C. K., Santulli, R. J., & Andrade-Gordon, P. (2001). Differential expression of protease activated receptors-1 and -2 in stromal fibroblasts of normal, benign, and malignant human tissues. American Journal of Pathology, 158, 2031–2041.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Zhao, F., Li, L., Guan, L., Yang, H., Wu, C., & Liu, Y. (2014). Roles for GP IIb/IIIa and αvβ3 integrins in MDA-MB-231 cell invasion and shear flow-induced cancer cell mechanotransduction. Cancer Letters, 344(1), 62–73.

    Article  CAS  PubMed  Google Scholar 

  58. Radjabi, A. R., Sawada, K., Jagadeeswaran, S., Eichbichler, A., Kenny, H. A., Montag, A., 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, 2822–2834.

    Article  CAS  PubMed  Google Scholar 

  59. Shi, X., Gangadharan, B., Brass, L., Ruf, W., & Mueller, B. (2004). Protease activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis. Molecular Cancer Research, 2, 395–402.

    CAS  PubMed  Google Scholar 

  60. Liotta, L. A., Steeg, P. S., & Stetler-Stevenson, W. (1991). Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell, 64, 327–336.

    Article  CAS  PubMed  Google Scholar 

  61. Hu, L., Roth, J. M., Brooks, P., Luty, J., & Karpatkin, S. (2008). Thrombin up-regulates cathepsin D which enhances angiogenesis, growth, and metastasis. Cancer Research, 68(12), 4666–4673.

    Article  CAS  PubMed  Google Scholar 

  62. Hu, L., Roth, J. M., Brooks, P., Ibrahim, S., & Karpatkin, S. (2008). Twist is required for thrombin-induced tumor angiogenesis and growth. Cancer Research, 68(11), 4296–4302.

    Article  CAS  PubMed  Google Scholar 

  63. Chang, L. H., Chen, C. H., Huang, D. Y., Pai, H. C., Pan, S. L., & Teng, C. M. (2011). Thrombin induces expression of twist and cell motility via the hypoxia-inducible factor-1α translational pathway in colorectal cancer cells. Journal of Cell Physiology, 226(4), 1060–1068.

    Article  CAS  Google Scholar 

  64. Beausoleil, M. S., Schulze, E. B., Goodale, D., Postenka, C. O., & Allan, A. L. (2011). Deletion of the thrombin cleavage domain of osteopontin mediates breast cancer cell adhesion, proteolytic activity, tumorgenicity, and metastasis. BioMed Central Cancer. doi:10.1186/1471-2407-11-25.

    PubMed  PubMed Central  Google Scholar 

  65. Rudland, P. S., Platt-Higgins, A., El-Tanani, M., De Silva Rudland, S., Barraclough, R., Winstanley, J. H., et al. (2002). Prognostic significance of the metastasis-associated protein osteopontin in human breast cancer. Cancer Research, 62, 3417–3427.

    CAS  PubMed  Google Scholar 

  66. Tuck, A. B., Chambers, A. F., & Allan, A. L. (2007). Osteopontin overexpression in breast cancer: knowledge gained and possible implications for clinical management. Journal of Cellular Biochemistry, 102(4), 859–868.

    Article  CAS  PubMed  Google Scholar 

  67. Senger, D., & Peruzzi, C. (1996). Cell migration promoted by a potent GRGDS-containing thrombin-cleavage fragment of osteopontin. Biochem et Biophysica Acta, 1314, 13–24.

    Article  CAS  Google Scholar 

  68. Senger, D. R., Ledbetter, S. R., Claffey, K. P., Papadopoulos-Sergiou, A., Peruzzi, C. A., & Detmar, M. (1996). Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the alphavbeta3 integrin, osteopontin, and thrombin. American Journal of Pathology, 149(1), 293–305.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Schulze, E. B., Hedley, B. D., Goodale, D., Postenka, C. O., Al-Katib, W., Tuck, A. B., et al. (2008). The thrombin inhibitor Argatroban reduces breast cancer malignancy and metastasis via osteopontin-dependent and osteopontin-independent mechanisms. Breast Cancer Research and Treatment, 112(2), 243–254.

    Article  CAS  PubMed  Google Scholar 

  70. Wallerand, H., Robert, G., Pasticier, G., Ravaud, A., Ballanger, P., Reiter, R. E., et al. (2010). The epithelial-mesenchymal transition-inducing factor TWIST is an attractive target in advanced and/or metastatic bladder and prostate cancers. Urologic Oncology, 28(5), 473–479.

    Article  CAS  PubMed  Google Scholar 

  71. Khan, M. A., Chen, H. C., Zhang, D., & Fu, J. (2013). Twist: a molecular target in cancer therapeutics. Tumour Biology, 34(5), 2497–2506.

    Article  CAS  PubMed  Google Scholar 

  72. Caunt, M., Hu, L., Tang, T., Brooks, P. C., Ibrahim, S., & Karpatkin, S. (2006). Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis. Cancer Research, 66(8), 4125–4132.

    Article  CAS  PubMed  Google Scholar 

  73. Even-Ram, S. C., Maoz, M., Pokroy, E., Reich, R., Katz, B. Z., Gutwein, P., 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 

  74. Bai, S. Y., Xu, N., Chen, C., Song, Y. L., Hu, J., & Bai, C. X. (2014). Integrin αvβ5 as a biomarker for the assessment of non-small cell lung cancer metastasis and overall survival. The Clinical Respiratory Journal. doi:10.1111/crj.12163.

    PubMed Central  Google Scholar 

  75. 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 

  76. Rásó, E., Tóvári, J., Tóth, K., Paku, S., Trikha, M., Honn, K. V., et al. (2001). Ectopic alphaIIbbeta3 integrin signaling involves 12-lipoxygenase- and PKC-mediated serine phosphorylation events in melanoma cells. Thrombosis and Haemostasis, 85(6), 1037–1042.

    PubMed  Google Scholar 

  77. Trikha, M., Timar, J., Zacharek, A., Nemeth, J. A., Cai, Y., Dome, B., et al. (2002). Role for beta3 integrins in human melanoma growth and survival. International Journal of Cancer, 101(2), 156–167.

    Article  CAS  PubMed  Google Scholar 

  78. Xu, Z., Zhu, L., Yao, M., Zhong, G., Dong, Q., & Yu, A. (2015). PTEN plays an important role in thrombin-mediated lung cancer cell functions. Biomed Research International. doi:10.1155/2015/459170.

    Google Scholar 

  79. Mußbach, F., Henklein, P., Westermann, M., Settmacher, U., Böhmer, F. D., & Kaufmann, R. (2014). Proteinase-activated receptor 1- and 4-promoted migration of Hep3B hepatocellular carcinoma cells depends on ROS formation and RTK transactivation. Journal of Cancer Research and Clinical Oncology, 141(5), 813–825.

    Article  PubMed  CAS  Google Scholar 

  80. Trejo, J., Connolly, A. J., & Coughlin, S. R. (1996). The cloned thrombin receptor is necessary and sufficient for activation of mitogen-activated protein kinase and mitogenesis in mouse lung fibroblasts. Loss of responses in fibroblasts from receptor knockout mice. Journal of Biological Chemistry, 271(35), 21536–21541.

    Article  CAS  PubMed  Google Scholar 

  81. Gratio, V., Walker, F., Lehy, T., Laburthe, M., & Darmoul, D. (2009). Aberrant expression of proteinase-activated receptor 4 promotes colon cancer cell proliferation through a persistent signaling that involves Src and ErbB-2 kinase. International Journal of Cancer, 124(7), 1517–1525.

    Article  CAS  PubMed  Google Scholar 

  82. Yuan, L., & Liu, X. (2015). Platelets are associated with xenograft tumor growth and the clinical malignancy of ovarian cancer through an angiogenesis-dependent mechanism. Molecular Medicine Reports, 11(4), 2449–2458.

    CAS  PubMed  Google Scholar 

  83. Schiller, H., Bartscht, T., Arlt, A., Zahn, M. O., Seifert, A., Bruhn, T., et al. (2002). Thrombin as a survival factor for cancer cells: thrombin activation in malignant effusions in vivo and inhibition of idarubicin-induced cell death in vitro. International Journal of Clinical Pharmacology and Therapeutics, 40(8), 329–335.

    Article  CAS  PubMed  Google Scholar 

  84. Pang, J. H., Coupland, L. A., Freeman, C., Chong, B. H., & Parish, C. R. (2015). Activation of tumour cell ECM degradation by thrombin-activated platelet membranes: potentially a P-selectin and GPIIb/IIIa-dependent process. Clinical & Experimental Metastasis, 32(5), 495–505.

    Article  CAS  Google Scholar 

  85. Janowska-Wieczorek, A., Wysoczynski, M., Kijowski, J., MarquezCurtis, L., Machalinski, B., Ratajczak, J., et al. (2005). Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. International Journal of Cancer, 113(5), 752–760.

    Article  CAS  PubMed  Google Scholar 

  86. Janowska-Wieczorek, A., Marquez-Curtis, L. A., Wysoczynski, M., & Ratajczak, M. Z. (2006). Enhancing effect of platelet-derived microvesicles on the invasive potential of breast cancer cells. Transfusion, 46(7), 1199–1209.

    Article  PubMed  Google Scholar 

  87. Lou, X. L., Sun, J., Gong, S. Q., Yu, X. F., Gong, R., & Deng, H. (2015). Interaction between circulating cancer cells and platelets: clinical implication. Chinese Journal of Cancer Research, 27(5), 450–460.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Labelle, M., Begum, S., & Hynes, R. O. (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 

  89. Cho, M. S., Bottsford-Miller, J., Vasquez, H. G., Stone, R., Zand, B., Kroll, M. H., et al. (2012). Platelets increase the proliferation of ovarian cancer cells. Blood, 120(24), 4869–4872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  91. Sierko, E., & Wojtukiewicz, M. Z. (2007). Inhibition of platelet function: does it offer a chance of better cancer progression control? Seminars in Thrombosis and Hemostasis, 33(7), 712–721.

    Article  CAS  PubMed  Google Scholar 

  92. Boucharaba, A., Serre, C. M., Grès, S., Saulnier-Blache, J. S., Bordet, J. C., Guglielmi, J., et al. (2004). Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. The Journal of Clinical Investment, 114(12), 1714–1725.

    Article  CAS  Google Scholar 

  93. 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 

  94. Koseoglu, S., & Flaumenhaft, R. (2013). Advances in platelet granule biology. Current Opinion in Hematology, 20(5), 464–471.

    Article  PubMed  Google Scholar 

  95. Martin, C. B., Mahon, G. M., Klinger, M. B., Kay, R. J., Symons, M., Der, C. J., 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 

  96. Steinbrecher, K. A., Horowitz, N. A., Blevins, E. A., Barney, K. A., Shaw, M. A., Harmel-Laws, E., et al. (2010). Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha(M)beta(2) engagement of fibrinogen. Cancer Research, 70, 2634–2643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Liu, C. Y., Nossel, H. L., & Kaplan, K. L. (1979). The binding of thrombin by fibrin. Journal of Biological Chemistry, 254(20), 10421–10425.

    CAS  PubMed  Google Scholar 

  98. Turpin, B., Miller, W., Rosenfeldt, L., Kombrinck, K., Flick, M. J., Steinbrecher, K. A., et al. (2014). Thrombin drives tumorigenesis in colitis-associated colon cancer. Cancer Research, 74(11), 3020–3030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sahni, A., & Francis, C. W. (2000). Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation. Blood, 96, 3772–3778.

    CAS  PubMed  Google Scholar 

  100. Mosesson, M. W. (2005). Fibrinogen and fibrin structure and functions. Journal of Thrombosis and Haemostasis, 3, 1894–1904.

    Article  CAS  PubMed  Google Scholar 

  101. Schachtrup, C., Ryu, J. K., Helmrick, M. J., Vagena, E., Galanakis, D. K., Degen, J. L., et al. (2010). Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage. Journal of Neuroscience, 30(17), 5843–5854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Palumbo, J. S., Potter, J. M., Kaplan, L. S., Talmage, K., Jackson, D. G., & Degen, J. L. (2002). Spontaneous hematogenous and lymphatic metastasis, but not primary tumor growth or angiogenesis, is diminished in fibrinogen-deficient mice. Cancer Research, 62, 6966–6972.

    CAS  PubMed  Google Scholar 

  103. Haralabopoulos, G., Grant, D., Kleinman, H., & Maragoudakis, M. (1997). Thrombin promotes endothelial cell alignment in Matrigel in vitro and angiogenesis in vivo. American Journal of Physiology, 273, C239–C245.

    CAS  PubMed  Google Scholar 

  104. Martínez, C. E., Smithm, P. C., & Palma Alvaradom, V. A. (2015). The influence of platelet-derived products on angiogenesis and tissue repair: a concise update. Frontiers in Physiology. doi:10.3389/fphys.2015.00290.

    PubMed  PubMed Central  Google Scholar 

  105. Posch, F., Thaler, J., Zlabinger, G. J., Königsbrügge, O., Koder, S., Zielinski, C., et al. (2016). Soluble vascular endothelial growth factor (sVEGF) and the risk of venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study (CATS). Clinical Cancer Research, 22(1), 200–206.

    Article  CAS  PubMed  Google Scholar 

  106. Ma, L., Perini, R., McKnight, W., Klein, A., Hollenberg, M. D., & Wallace, J. L. (2005). Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. Proceedings of the National Academy of Sciences of the United States of America, 102, 216.

    Article  CAS  PubMed  Google Scholar 

  107. Ekambaram, P., Lambiv, W., Cazzolli, R., Ashton, A. W., & Honn, K. V. (2011). The thromboxane synthase and receptor signaling pathway in cancer: an emerging paradigm in cancer progression and metastasis. Cancer Metastasis Reviews, 30(3–4), 397–408.

    Article  CAS  PubMed  Google Scholar 

  108. Honn, K. V. (1983). Inhibition of tumor cell metastasis by modulation of the vascular prostacyclin/thromboxane A2 system. Clinical and Experimental Metastasis, 1(2), 103–14.

    Article  CAS  PubMed  Google Scholar 

  109. Honn, K. V., Grossi, I. M., Fitzgerald, L. A., Umbarger, L. A., Diglio, C. A., et al. (1988). Lipoxygenase products regulate IRGpIIb/IIIa receptor mediated adhesion of tumor cells to endothelial cells, subendothelial matrix and fibronectin. Proceedings of the Society for Experimental Biology and Medicine, 189(1), 130–135.

    Article  CAS  PubMed  Google Scholar 

  110. Honn, K. V., Tang, D. G., & Chen, Y. Q. (1992). Platelets and cancer metastasis: more than an epiphenomenon. Seminars in Thrombosis and Hemostasis, 18(4), 392–415.

    Article  CAS  PubMed  Google Scholar 

  111. Honn, K. V., Tang, D. G., Grossi, I. M., Renaud, C., Duniec, Z. M., Johnson, C. R., et al. (1994). Enhanced endothelial cell retraction mediated by 12(S)-HETE: a proposed mechanism for the role of platelets in tumor cell metastasis. Experimental Cell Research, 210(1), 1–9.

    Article  CAS  PubMed  Google Scholar 

  112. Steinert, B. W., Tang, D. G., Grossi, I. M., Umbarger, L. A., & Honn, K. V. (1993). Studies on the role of platelet eicosanoid metabolism and integrin alpha IIb beta 3 in tumor-cell-induced platelet aggregation. International Journal of Cancer, 54(1), 92–101.

    Article  CAS  PubMed  Google Scholar 

  113. Chen, Y. Q., Hagmann, W., & Honn, K. V. (1997). Regulation of 12(S)-HETE production in tumor cells. Advances in Experimental Medicine and Biology, 400A, 159–66.

    Article  CAS  PubMed  Google Scholar 

  114. Tang, D. G., Diglio, C. A., & Honn, K. V. (1993). 12(S)-HETE-induced microvascular endothelial cell retraction results from PKC-dependent rearrangement of cytoskeletal elements and alpha V beta 3 integrins. Prostaglandins, 45(3), 249–67.

    Article  CAS  PubMed  Google Scholar 

  115. Tang, D. G., Chen, Y. Q., Diglio, C. A., & Honn, K. V. (1993). Protein kinase C-dependent effects of 12(S)-HETE on endothelial cell vitronectin receptor and fibronectin receptor. Journal of Cell Biology, 121(3), 689–704.

    Article  CAS  PubMed  Google Scholar 

  116. Krishnamoorthy, S., Jin, R., Cai, Y., Maddipati, K. R., Nie, D., Pagès, G., et al. (2010). 12-Lipoxygenase and the regulation of hypoxia-inducible factor in prostate cancer cells. Experimental Cell Research, 316(10), 1706–1715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Krishnamoorthy, S., & Honn, K. V. (2011). Eicosanoids and other lipid mediators and the tumor hypoxic microenvironment. Cancer Metastasis Reviews, 30(3–4), 613–618.

    Article  CAS  PubMed  Google Scholar 

  118. Krishnamoorthy, S., & Honn, K. V. (2008). Eicosanoids in tumor progression and metastasis. Subcellular Biochemistry, 49, 145–168.

    Article  PubMed  Google Scholar 

  119. Tucker, S. C., & Honn, K. V. (2013). Emerging targets in lipid-based therapy. Biochemical Pharmacology, 85(5), 673–688.

    Article  CAS  PubMed  Google Scholar 

  120. Dilly, A. K., Ekambaram, P., Guo, Y., Cai, Y., Tucker, S. C., Fridman, R., et al. (2013). Platelet-type 12-lipoxygenase induces MMP9 expression and cellular invasion via activation of PI3K/Akt/NF-κB. International Journal of Cancer, 133(8), 1784–1791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Pidgeon, G. P., Lysaght, J., Krishnamoorthy, S., Reynolds, J. V., O’Byrne, K., Nie, D., et al. (2007). Lipoxygenase metabolism: roles in tumor progression and survival. Cancer Metastasis Reviews, 26(3–4), 503–524.

    Article  CAS  PubMed  Google Scholar 

  122. Pidgeon, G. P., Tang, K., Cai, Y. L., Piasentin, E., & Honn, K. V. (2003). Overexpression of platelet-type 12-lipoxygenase promotes tumor cell survival by enhancing alpha(v)beta(3) and alpha(v)beta(5) integrin expression. Cancer Research, 63(14), 4258–4267.

    CAS  PubMed  Google Scholar 

  123. Rásó, E., Döme, B., Somlai, B., Zacharek, A., Hagmann, W., Honn, K. V., et al. (2004). Molecular identification, localization and function of platelet-type 12-lipoxygenase in human melanoma progression, under experimental and clinical conditions. Melanoma Research, 14(4), 245–250.

    Article  PubMed  CAS  Google Scholar 

  124. Tang, K., Cai, Y., Joshi, S., Tovar, E., Tucker, S. C., Maddipati, K. R., et al. (2015). Convergence of eicosanoid and integrin biology: 12-lipoxygenase seeks a partner. Molecular Cancer, 3(14), 111.

    Article  CAS  Google Scholar 

  125. Timar, J., Bazaz, R., Tang, D. G., Kimler, V., Taylor, J. D., & Honn, K. V. (1997). Post-translational regulation of surface integrin expression in tumor cells by 12(S)-HETE. Advances in Experimental Medicine and Biology, 400B, 757–763.

    CAS  PubMed  Google Scholar 

  126. Maragoudakis, M. E., Tsopanoglou, N. E., & Andriopoulou, P. (2002). Mechanism of thrombin-induced angiogenesis. Biochemical Society Transactions, 30(2), 173–177.

    Article  CAS  PubMed  Google Scholar 

  127. 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 Therapeutics, 318, 246–254.

    Article  CAS  PubMed  Google Scholar 

  128. Tsopanoglou, N. E., & Maragoudakis, M. E. (1999). On the mechanism of thrombin-induced angiogenesis: potentiation of vascular endothelial growth factor activity on endothelial cells by upregulation of its receptors. Journal of Biological Chemistry, 274(34), 23969–23976.

    Article  CAS  PubMed  Google Scholar 

  129. Tsopanoglou, N. E., Andriopoulou, P., & Maragoudakis, M. E. (2002). On the mechanism of thrombin-induced angiogenesis: involvement of alphavbeta3-integrin. American Journal of Physiology. Cell Physiology, 83(5), C1501–1510.

    Article  Google Scholar 

  130. Andrikopoulos, P., Kieswich, J., Harwood, S. M., Baba, A., Matsuda, T., Barbeau, O., et al. (2015). Endothelial angiogenesis and barrier function in response to thrombin require Ca2+ influx through the Na+/Ca2+ exchanger. The Journal of Biological Chemistry, 290(30), 18412–18428.

    Article  CAS  PubMed  Google Scholar 

  131. Olivot, J. M., Estebanell, E., Lafay, M., Brohard, B., Aiach, M., & Rendu, F. (2001). Thrombomodulin prolongs thrombin-induced extracellular signal-regulated kinase phosphorylation and nuclear retention in endothelial cells. Circulation Research, 88, 681.

    Article  CAS  PubMed  Google Scholar 

  132. D’Asti, E., Kool, M., Pfister, S. M., & Rak, J. (2014). Coagulation and angiogenic gene expression profiles are defined by molecular subgroups of medulloblastoma: evidence for growth factor-thrombin cross-talk. Journal of Thrombosis and Haemostasis, 12(11), 1838–1849.

    Article  PubMed  CAS  Google Scholar 

  133. Xu, Y., Gu, Y., Keep, R. F., Heth, J., Muraszko, K. M., Xi, G., et al. (2009). Thrombin up-regulates vascular endothelial growth factor in experimental gliomas. Neurological Research, 31(7), 759–765.

    Article  CAS  PubMed  Google Scholar 

  134. Zania, P., Gourni, D., Aplin, A. C., Nicosia, R. F., Flordellis, C. S., Maragoudakis, M. E., et al. (2009). Parstatin, the cleaved peptide on proteinase-activated receptor 1 activation, is a potent inhibitor of angiogenesis. Journal of Pharmacology and Experimental Therapeutics, 328(2), 378–389.

    Article  CAS  PubMed  Google Scholar 

  135. Koolwijk, P., van Erck, M. G., de Vree, W. J., Vermeer, M. A., Weich, H. A., Hanemaaijer, R., et al. (1996). Cooperative effect of TNF-alpha, bFGF, and VEGF on the formation of tubular structures of human microvascular endothelial cells in a fibrin matrix. Role of urokinase activity. Journal of Cellular Biology, 132, 1177.

    Article  CAS  Google Scholar 

  136. Mittermayr, R., Slezak, P., Haffner, N., Smolen, D., Hartinger, J., Hofmann, A., et al. (2016). Controlled release of fibrin matrix-conjugated platelet derived growth factor improves ischemic tissue regeneration by functional angiogenesis. Acta Biomaterialia, 29, 11–20.

    Article  CAS  PubMed  Google Scholar 

  137. Smadja, D. M., Basire, A., Amelot, A., Conte, A., Bièche, I., Le Bonniec, B. F., et al. (2008). Thrombin bound to a fibrin clot confers angiogenic and haemostatic properties on endothelial progenitor cells. Journal of Cellular and Molecular Medicine, 12, 975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Jolly, M. K., Boareto, M., Huang, B., Jia, D., Lu, M., Ben-Jacob, E., et al. (2015). Implications of the hybrid epithelial/mesenchymal phenotype in metastasis. Frontiers in Oncology. doi:10.3389/fonc.2015.00155.

    PubMed  PubMed Central  Google Scholar 

  139. Talmadge, J. E., & Fidler, I. J. (2010). AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Research, 70(14), 5649–5669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Liu, H., Zhang, X., Li, J., Sun, B., Qian, H., & Yin, Z. (2015). The biological and clinical importance of epithelial-mesenchymal transition in circulating tumor cells. Journal of Cancer Research and Clinical Oncology, 141(2), 189–201.

    Article  CAS  PubMed  Google Scholar 

  141. Ozdemir, T., Zhang, P., Fu, C., & Dong, C. (2012). Fibrin serves as a divalent ligand that regulates neutrophil-mediated melanoma cells adhesion to endothelium under shear conditions. American Journal of Physiology - Cell Physiology, 302(8), C1189–1201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 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, 2287–2294.

    CAS  PubMed  Google Scholar 

  143. Pavese, J. M., & Bergan, R. C. (2014). Circulating tumor cells exhibit a biologically aggressive cancer phenotype accompanied by selective resistance to chemotherapy. Cancer Letters, 352(2), 179–186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Lecharpentier, A., Vielh, P., Perez-Moreno, P., Planchard, D., Soria, J. C., & Farace, F. (2011). Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer. British Journal of Cancer, 105, 1338–1341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Hou, J. M., Krebs, M., Ward, T., Sloane, R., Priest, L., Hughes, A., et al. (2011). Circulating tumor cells as a window on metastasis biology in lung cancer. The American Journal of Pathology, 178, 989–996.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Armstrong, A. J., Marengo, M. S., Oltean, S., Kemeny, G., Bitting, R. L., Turnbull, J. D., et al. (2011). Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Molecular Cancer Research, 9, 997–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Konstantoulaki, M., Kouklis, P., & Malik, A. B. (2003). Protein kinase C modifications of VE-cadherin, p120, and beta-catenin contribute to endothelial barrier dysregulation induced by thrombin. American Journal of Physiology Lung Cellular and Molecular Physiology, 285, L434–442.

    Article  CAS  PubMed  Google Scholar 

  148. Yokota, N., Zarpellon, A., Chakrabarty, S., Bogdanov, V. Y., Gruber, A., Castellino, F. J., et al. (2014). Contributions of thrombin targets to tissue factor-dependent metastasis in hyperthrombotic mice. Journal of Thrombosis and Haemostasis, 12(1), 71–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Crissman, J. D., Hatfield, J., Schaldenbrand, M., Sloane, B. F., & Honn, K. V. (1985). Arrest and extravasation of B16 amelanotic melanoma in murine lungs. A light and electron microscopic study. Laboratory Investigation, 53(4), 470–478.

    CAS  PubMed  Google Scholar 

  150. Crissman, J. D., Hatfield, J. S., & Honn, K. V. (1986). Clinical and experimental morphologic parameters predictive of tumor metastasis. Progress in Clinical and Biological Research, 212, 251–267.

    CAS  PubMed  Google Scholar 

  151. Crissman, J. D., Hatfield, J. S., Menter, D. G., Sloane, B., & Honn, K. V. (1988). Morphological study of the interaction of intravascular tumor cells with endothelial cells and subendothelial matrix. Cancer Research, 48(14), 4065–4072.

    CAS  PubMed  Google Scholar 

  152. Qian, W., Tao, L., Wang, Y., Zhang, F., Li, M., Huang, S., et al. (2015). Downregulation of integrins in cancer cells and anti-platelet properties are involved in Holothurian glycosaminoglycan-mediated disruption of the interaction of cancer cells and platelets in hematogenous metastasis. Journal of Vascular Research, 52(3), 197–209.

    Article  CAS  PubMed  Google Scholar 

  153. Lova, P., Canobbio, I., Guidetti, G. F., Balduini, C., & Torti, M. (2010). Thrombin induces platelet activation in the absence of functional protease activated receptors 1 and 4 and glycoprotein Ib-IX-V. Cellular Signalling, 22(11), 1681–1687.

    Article  CAS  PubMed  Google Scholar 

  154. De Candia, E., Hall, S. W., Rutella, S., Landolfi, R., Andrews, R. K., & De Cristofaro, R. (2001). Binding of thrombin to glycoprotein Ib accelerates the hydrolysis of Par-1 on intact platelets. The Journal of Biological Chemistry, 276, 4692–4698.

    Article  PubMed  Google Scholar 

  155. Tanaka, N. G., Tohgo, A., & Ogawa, H. (1986). Platelet-aggregating activities of metastasizing tumor cells. V. In situ roles of platelets in hematogenous metastases. Invasion & Metastasis, 6(4), 209–224.

    CAS  Google Scholar 

  156. Gasic, G., Gasic, T., Galanti, N., Johnson, T., & Murphy, S. (1973). Platelet tumor-cell interactions in mice. The role of platelets in the spread of malignant disease. International Journal of Cancer, 11, 704–718.

    Article  CAS  PubMed  Google Scholar 

  157. Oleksowicz, L., Mrowiec, Z., Schwartz, E., Khorshidi, M., Dutcher, J. P., & Puszkin, E. (1995). Characterization of tumor-induced platelet aggregation: the role of immunorelated GPIb and GPIIb/IIIa expression by MCF-7 breast cancer cells. Thrombosis Research, 79(3), 261–274.

    Article  CAS  PubMed  Google Scholar 

  158. Naimushin, Y. A., & Mazurov, A. V. (2004). Von Willebrand factor can support platelet aggregation via interaction with activated GPIIb-IIIa and GPIb. Platelets, 15(7), 419–425.

    Article  CAS  PubMed  Google Scholar 

  159. Naimushin, Y. A., & Mazurov, A. V. (2005). Ability of different glycoprotein IIb-IIIa ligands to support platelet aggregation induced by activating antibody CRC54. Biochemistry (Mosc), 70(7), 782–789.

    Article  CAS  Google Scholar 

  160. Ünlü, B., & Versteeg, H. H. (2014). Effects of tumor-expressed coagulation factors on cancer progression and venous thrombosis: is there a key factor? Thrombosis Research, 133(Suppl 2), S76–84.

    Article  PubMed  CAS  Google Scholar 

  161. Maskrey, B. H., Bermúdez-Fajardo, A., Morgan, A. H., Stewart-Jones, E., Dioszeghy, V., Taylor, G. W., et al. (2007). Activated platelets and monocytes generate four hydroxyphosphatidylethanolamines via lipoxygenase. The Journal of Biological Chemistry, 282(28), 20151–20163.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  163. Ohana, O. M., Ozer, J., Prinsloo, I., Benharroch, D., & Gopas, J. (2015). Hodgkin lymphoma cell lines bind to platelets. Incubation with platelets induces CD15 and P-selectin dependent adhesion of the cell lines to human umbilical vein endothelial cells (HUVEC). Cancer Biology and Therapy, 16(11), 1651–1659.

    Article  CAS  PubMed  Google Scholar 

  164. Fidler, I. (1970). Metastases: quantitative analysis of distribution and fate of tumor emboli labeled with 125I-5-iodo-2′-deoxyuridine. Journal of National Cancer Institute, 45, 773–782.

    CAS  Google Scholar 

  165. Coupland, L. A., Chong, B. H., & Parish, C. R. (2012). Platelets and P-selectin control tumor cell metastasis in an organ-specific manner and independently of NK cells. Cancer Research, 72(18), 4662–4671.

    Article  CAS  PubMed  Google Scholar 

  166. Palumbo, J. S., Talmage, K. E., Massari, J. V., La Jeunesse, C. M., Flick, M. J., Kombrinck, K. W., et al. (2005). Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood, 105, 178.

    Article  CAS  PubMed  Google Scholar 

  167. Placke, T., Orgel, M., Schaller, M., Jung, G., Rammensee, H. G., Kopp, H. G., et al. (2012). Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Research, 72, 440–448.

    Article  CAS  PubMed  Google Scholar 

  168. Jain, S., Zuka, M., Liu, J., Russell, S., Dent, J., Guerrero, J. A., et al. (2007). Platelet glycoprotein Ib alpha supports experimental lung metastasis. Proceedings of the National Academy of Sciences of the United States of America, 104(21), 9024–9028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Boukerche, H., Berthier-Vergnes, O., Tabone, E., Dore, J., Leung, L., & McGregor, J. (1989). Platelet-melanoma cell interaction is mediated by the glycoprotein IIb-IIIa complex. Blood, 74, 658–663.

    CAS  PubMed  Google Scholar 

  170. McGregor, B., McGregor, J., Weiss, L., Wood, G., Hu, C., Boukerche, H., et al. (1989). Presence of cytoadhesins (IIb-IIIa-like glycoproteins) on human metastatic melanomas but not on benign melanocytes. American Journal of Clinical Pathology, 92, 495–499.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  172. Aigner, S., Ramos, C., Hafezi-Moghadam, A., Lawrence, M., Friederichs, J., Altevogt, P., et al. (1998). CD24 mediates rolling of breast carcinoma cells on P-selectin. Federation of American Societies for Experimental Biology Journal, 12, 1241–1251.

    CAS  PubMed  Google Scholar 

  173. Lou, X. L., Deng, J., Deng, H., Ting, Y., Zhou, L., Liu, Y. H., et al. (2014). Aspirin inhibit platelet-induced epithelial-to-mesenchymal transition of circulating tumor cells (review). Biomedical Reports, 2(3), 331–334.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Humphries, M., Olden, K., & Yamada, K. (1986). A synthetic peptide from fibronectin inhibits experimental metastases of murine melanoma cells. Science, 467, 467–470.

    Article  Google Scholar 

  175. Klepfish, A., Greco, M., & Karpatkin, S. (1993). Thrombin stimulates melanoma tumor-cell binding to endothelial cells and subendothelial matrix. International Journal of Cancer, 53, 978–982.

    Article  CAS  PubMed  Google Scholar 

  176. Dardik, R., Savion, N., Kaufmann, Y., & Varon, D. (1998). Thrombin promotes platelet-mediated melanoma cell adhesion to endothelial cells under flow conditions: role of platelet glycoproteins P-selectin and GPIIb-IIIa. British Journal of Cancer, 77, 2069–2075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Wang, J., Xiao, J., Wen, D., Wu, X., Mao, Z., Zhang, J., et al. (2016). Endothelial cell-anchored tissue factor pathway inhibitor regulates tumor metastasis to the lung in mice. Molecular Carcinogenesis, 55(5), 882–896.

    Article  CAS  PubMed  Google Scholar 

  178. Nie, D., Tang, K., Szekeres, K., Trikha, M., & Honn, K. V. (2000). The role of eicosanoids in tumor growth and metastasis. Ernst Schering Research Foundation Workshop Journal, 31, 201–217.

    CAS  Google Scholar 

  179. Honn, K. V., Tang, D. G., Grossi, I., Duniec, Z. M., Timar, J., Renaud, C., et al. (1994). Tumor cell-derived 12(S)-hydroxyeicosatetraenoic acid induces microvascular endothelial cell retraction. Cancer Research, 54(2), 565–574.

    CAS  PubMed  Google Scholar 

  180. Weiler, H., & Isermann, B. H. (2003). Thrombomodulin. Journal of Thrombosis and Haemostasis, 1, 1515–1524.

    Article  CAS  PubMed  Google Scholar 

  181. Van Sluis, G. L., Niers, T. M., Esmon, C. T., Tigchelaar, W., Richel, D. J., & Buller, H. R. (2009). Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1-mediated vascular endothelial barrier enhancement. Blood, 114(9), 1968–1973.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Palumbo, J. S., Kombrinck, K. W., Drew, A. F., Grimes, T. S., Kiser, J. H., Degen, J. L., et al. (2000). Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood, 96, 3302.

    CAS  PubMed  Google Scholar 

  183. Palumbo, J. S. (2008). Mechanisms linking tumor cell-associated procoagulant function to tumor dissemination. Seminars in Thrombosis and Hemostasis, 34, 154–160.

    Article  CAS  PubMed  Google Scholar 

  184. Palumbo, J.S., Talmage, K.E., Massari, J.V., La Jeunesse, C.M., Flick, M.J., Kombrinck, K.W., et al. (2007). Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and -independent mechanisms. Blood. 19.

  185. Palumbo, J. S., Barney, K. A., Blevins, E. A., Shaw, M. A., Mishra, A., Flick, M. J., et al. (2008). Factor XIII transglutaminase supports hematogenous tumor cell metastasis through a mechanism dependent on natural killer cell function. Journal of Thrombosis and Haemostasis, 6, 812–819.

    Article  CAS  PubMed  Google Scholar 

  186. Biggerstaff, J. P., Seth, N., Amirkhosravi, A., Amaya, M., Fogarty, S., Meyer, T. V., Siddiqui, F., Francis, J. L., et al. (1999). Soluble fibrin augments platelet/tumor cell adherence in vitro and in vivo, and enhances experimental metastasis. Clinical & Experimental Metastasis, 17, 723–730.

    Article  CAS  Google Scholar 

  187. Zhang, P., Ozdemir, T., Chung, C. Y., Robertson, G. P., & Dong, C. (2011). Sequential binding of α(v)β(3) and ICAM-1 determines fibrin-mediated melanoma capture and stable adhesion to CD11b/CD18 on neutrophils. Journal of Immunology, 186, 242–254.

    Article  CAS  Google Scholar 

  188. Gaddes, E. R., Lee, D., Gydush, G., Wang, Y., & Dong, C. (2015). Regulation of fibrin-mediated tumor cell adhesion to the endothelium using anti-thrombin aptamer. Experimental Cell Research. doi:10.1016/j.yexcr.2015.10.010.

    PubMed  Google Scholar 

  189. Yokoyama, K., Erickson, H. P., Ikeda, Y., & Takada, Y. (2000). Identification of amino acid sequences in fibrinogen γ-chain and tenascin CC-terminal domains critical for binding to integrin α(v)β(3). Journal of Biological Chemistry, 275, 16891–16898.

    Article  CAS  PubMed  Google Scholar 

  190. Lee, S. H., Suh, I. B., Lee, E. J., Hur, G. Y., Lee, S. Y., Lee, S. Y., et al. (2013). Relationships of coagulation factor XIII activity with cell-type and stage of non-small cell lung cancer. Yonsei Medical Journal, 54(6), 1394–1399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Vairaktaris, E., Vassiliou, S., Yapijakis, C., Spyridonidou, S., Vylliotis, A., Derka, S., et al. (2007). Increased risk for oral cancer is associated with coagulation factor XIII but not with factor XII. Oncology Reports, 18, 1537–1543.

    CAS  PubMed  Google Scholar 

  192. An, Y., Bekesova, S., Edwards, N., & Goldman, R. (2010). Peptides in low molecular weight fraction of serum associated with hepatocellular carcinoma. Disease Markers, 29, 11–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Kiss, F., Hevessy, Z., Veszprémi, A., Katona, E., Kiss, C., Vereb, G., et al. (2006). Leukemic lymphoblasts, a novel expression site of coagulation factor XIII subunit A. Thrombosis and Haemostasis, 96, 176–182.

    CAS  PubMed  Google Scholar 

  194. Andersson, C., Kvist, P. H., McElhinney, K., Baylis, R., Gram, L. K., Pelzer, H., et al. (2015). Factor XIII transglutaminase supports the resolution of mucosal damage in experimental colitis. Public Library of Science One, 10(6), e0128113.

    PubMed  PubMed Central  Google Scholar 

  195. Menter, D. G., Hatfield, J. S., Harkins, C., Sloane, B. F., Taylor, J. D., Crissman, J. D., et al. (1987). Tumor cell-platelet interactions in vitro and their relationship to in vivo arrest of hematogenously circulating tumor cells. Clinical and Experimental Metastasis, 5(1), 65–78.

    Article  CAS  PubMed  Google Scholar 

  196. Helland, I., Klemensten, B., & Jorgensen, L. (1997). Addition of both platelets and thrombin in combination accelerates tumor cells to adhere to endothelial cells in vitro. In Vitro Cellular & Developmental Biology, 33, 182–186.

    Article  CAS  Google Scholar 

  197. Pilch, J., Habermann, R., & Felding-Habermann, B. (2002). Unique ability of integrin alpha(v)beta 3 to support tumor cell arrest under dynamic flow conditions. The Journal of Biological Chemistry, 277(24), 21930–21938.

    Article  CAS  PubMed  Google Scholar 

  198. Chen, Y. Q., & Honn, K. V. (1993). Eicosanoid regulation of tumor cell-platelet and -endothelium interaction during arrest and extravasation. In S. Nigam, K. Honn, L. Barnett, & T. Walden Jr. (Eds.), Developments in oncology. Eicosanoids and other bioactive lipids in cancer, inflammation and radiation injury (Vol. 71, pp. 613–617). New York: Springer.

  199. Chen, Y. Q., Duniec, Z. M., Liu, B., Hagmann, W., Gao, X., Shimoji, K., et al. (1994). Endogenous 12(S)-HETE production by tumor cells and its role in metastasis. Cancer Research, 54(6), 1574–1579.

    CAS  PubMed  Google Scholar 

  200. Baserga, R., & Saffiotti, U. (1955). Experimental studies on histogenesis of blood-borne metastases. AMA Archives of Pathology, 59(1), 26–34.

    CAS  PubMed  Google Scholar 

  201. Schumacher, D., Strilic, B., Sivaraj, K. K., Wettschureck, N., & Offermanns, S. (2013). Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 receptor. Cancer Cell, 24(1), 130–137.

    Article  CAS  PubMed  Google Scholar 

  202. Khuon, S., Liang, L., Dettman, R. W., Sporn, P. H., Wysolmerski, R. B., & Chew, T. L. (2010). Myosin light chain kinase mediates transcellular intravasation of breast cancer cells through the underlying endothelial cells: a three-dimensional FRET study. Journal of Cellular Science, 123(Pt 3), 431–440.

    Article  CAS  Google Scholar 

  203. Mierke, C. T., Zitterbart, D. P., Kollmannsberger, P., Raupach, C., Schlotzer-Schrehardt, U., Goecke, T. W., et al. (2008). Breakdown of the endothelial barrier function in tumor cell transmigration. Biophysical Journal, 94, 2832–2846.

    Article  CAS  PubMed  Google Scholar 

  204. Dejana, E., Orsenigo, F., & Lampugnani, M. G. (2008). The role of adherens junctions and VE-cadherin in the control of vascular permeability. Journal of Cell Science, 121(Pt 13), 2115–2122.

    Article  CAS  PubMed  Google Scholar 

  205. Dudek, S. M., & Garcia, J. G. (2001). Cytoskeletal regulation of pulmonary vascular permeability. Journal of Applied Physiology, 91, 1487–1500.

    CAS  PubMed  Google Scholar 

  206. Rabiet, M. J., Plantier, J. L., Rival, Y., Genoux, Y., Lampugnani, M. G., & Dejana, E. (1996). Thrombin-induced increase in endothelial permeability is associated with changes in cell-to-cell junction organization. Arteriosclerosis, Thrombosis, and Vascular Biology, 16, 488–496.

    Article  CAS  PubMed  Google Scholar 

  207. Vincent, P. A., Xiao, K., Buckley, K. M., & Kowalczyk, A. P. (2004). VE-cadherin: adhesion at arm’s length. American Journal o Physiology - Cell Physiology, 286(5), C987–997.

    Article  CAS  Google Scholar 

  208. Potter, M. D., Barbero, S., & Cheresh, D. A. (2005). Tyrosine phosphorylatio of VE-cadherin prevents binding of p120- and beta-catenin and maintains the cellular mesenchymal state. Journal of Biological Chemistry, 280, 31906–31912.

    Article  CAS  PubMed  Google Scholar 

  209. Sandoval, R., Malik, A. B., Minshall, R. D., Kouklis, P., Ellis, C. A., & Tiruppathi, C. (2001). Ca(2+) signalling and PKCalpha activate increased endothelial permeability by disassembly of VE-cadherin junctions. Journal of Physiology, 533(Pt 2), 433–445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Stockton, R. A., Schaefer, E., & Schwartz, M. A. (2004). p21-activated kinase regulates endothelial permeability through modulation of contractility. Journal of Biological Chemistry, 279(45), 46621–46630.

    Article  CAS  PubMed  Google Scholar 

  211. Hugo, H., Ackland, M. L., Blick, T., Lawrence, M. G., Clements, J. A., & Williams, E. D. (2007). Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. Journal of Cell Physiology, 213(2), 374–383.

    Article  CAS  Google Scholar 

  212. 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 

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

    CAS  PubMed  Google Scholar 

  214. Rousseau, A., Van Dreden, P., Mbemba, E., Elalamy, I., Larsen, A., & Gerotziafas, G. T. (2015). Cancer cells BXPC3 and MCF7 differentially reverse the inhibition of thrombin generation by apixaban, fondaparinux and enoxaparin. Thrombosis Research, 136(6), 1273–1279.

    Article  CAS  PubMed  Google Scholar 

  215. Villares, G. J., Zigler, M., Wang, H., Melnikova, V. O., Wu, H., Friedman, R., et al. (2008). Targeting melanoma growth and metastasis with systemic delivery of liposome-incorporated protease-activated receptor-1 small interfering RNA. Cancer Research, 68, 9078–9086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Cowan, C., Muraleedharan, C. K., O’Donnell, J. J., Singh, P. K., Lum, H., Kumar, A., et al. (2014). MicroRNA-146 inhibits thrombin-induced NF-κB activation and subsequent inflammatory responses in human retinal endothelial cells. Investigative Ophthalmology and Visual Science, 55(8), 4944–4951.

    Article  CAS  PubMed  Google Scholar 

  217. Saleiban, A., Faxälv, L., Claesson, K., Jönsson, J. I., & Osman, A. (2014). miR-20b regulates expression of proteinase-activated receptor-1 (PAR-1) thrombin receptor in melanoma cells. Pigment Cell & Melanoma Research, 27(3), 431–441.

    Article  CAS  Google Scholar 

  218. Wang, H. J., Huang, Y. L., Shih, Y. Y., Wu, H. Y., Peng, C. T., & Lo, W. Y. (2014). MicroRNA-146a decreases high glucose/thrombin-induced endothelial inflammation by inhibiting NAPDH oxidase 4 expression. Mediators of Inflammation. doi:10.1155/2014/379537.

    Google Scholar 

  219. Sun, X., Lin, J., He, S., Franck, G., Wara, A., Icli, B., Li, D., & Feinberg, M. W. (2015). MicroRNA-181b inhibits thrombin-mediated activation of endothelial cells and arterial thrombosis by targeting card10. Circulation, 132, A12208.

    Google Scholar 

  220. Peng, C. T., Lo, W. Y., & Wang, H. J. (2014). High glucose/thrombin-induced endothelial inflammation via microRNA-146a and Nox4 regulation. Blood, 124(21), 5952–5952.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, Medical University of Bialystok, 12 Ogrodowa St., 15-025, Bialystok, Poland

    Marek Z. Wojtukiewicz, Dominika Hempel & Ewa Sierko

  2. Department of Clinical Oncology, Comprehensive Cancer Center in Bialystok, Bialystok, Poland

    Marek Z. Wojtukiewicz

  3. Department of Radiotherapy, Comprehensive Cancer Center in Bialystok, Bialystok, Poland

    Dominika Hempel & Ewa Sierko

  4. Bioactive Lipids Research Program, Department of Pathology-School of Medicine, Wayne State University, Detroit, MI, USA

    Stephanie C. Tucker & Kenneth V. Honn

  5. Department of Chemistry, Wayne State University, Detroit, MI, USA

    Kenneth V. Honn

  6. Department of Oncology, Karmanos Cancer Institute, Detroit, MI, USA

    Kenneth V. Honn

Authors
  1. Marek Z. Wojtukiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dominika Hempel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ewa Sierko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephanie C. Tucker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenneth V. Honn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marek Z. Wojtukiewicz.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wojtukiewicz, M.Z., Hempel, D., Sierko, E. et al. Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis. Cancer Metastasis Rev 35, 213–233 (2016). https://doi.org/10.1007/s10555-016-9626-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-016-9626-0

Keywords

Search

Navigation