Molecular Medicine

, Volume 10, Issue 1–6, pp 6–11 | Cite as

Tissue Factor and Cancer Metastasis: The Role of Intracellular and Extracellular Signaling Pathways

  • Henri H. Versteeg
  • C. Arnold Spek
  • Maikel P. Peppelenbosch
  • Dick J. Richel
In Overview


Tissue factor (TF) initiates the coagulation cascade but also plays a role in cancer and metastasis. This transmembrane protein is frequently upregulated on tumor cells and cells that show metastatic behavior. Furthermore, it is a significant risk factor for hepatic metastasis in patients suffering from colon cancer. Recently, it has been shown that TF, together with its natural ligand factor VIIa, induces intracellular changes, such as signal transduction cascades, gene transcription, and protein synthesis. Moreover, TF:factor VIIa interaction leads to survival of cells that have been stimulated to undergo apoptosis. Together with TF-dependent processes such as angiogenesis, these intracellular phenomena form a plausible explanation for the influence of TF on metastasis. In this review, we will discuss these phenomena in more detail and hypothesize on their role in TF-driven metastasis.


  1. 1.
    Fidler IJ. (1990) Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res. 50:6130–8.PubMedGoogle Scholar
  2. 2.
    Fidler IJ. (1990) Host and tumor factors in cancer metastasis. Eur. J. Clin. Invest. 20:481–6.CrossRefGoogle Scholar
  3. 3.
    Bach RR. (1988) Initiation of coagulation by tissue factor. CRC Crit. Rev. Biochem. 23:339–68.CrossRefGoogle Scholar
  4. 4.
    Bazan JF. (1990) Structural design and molecular evolution of a cytokine receptor superfamily. Proc. Natl. Acad. Sci. U.S.A. 87:6934–8.CrossRefGoogle Scholar
  5. 5.
    Drake TA, Morrisey JH, Edgington TS. (1989) Selective cellular expression of tissue factor in human tissues: implications for disorders of hemostasis and thrombosis. Am. J. Pathol. 134:1087–97.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Wilcox JN, Smith KM, Schwartz SM. (1989) Localisation of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc. Natl. Acad. Sci. U.S.A. 86:2839–43.CrossRefGoogle Scholar
  7. 7.
    Fleck RA, Rao LVM, Rapaport SI, Varki N. (1990) Localisation of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody. Thromb. Res. 57:765–81.CrossRefGoogle Scholar
  8. 8.
    Montemurro P et al. (1985) Increased in vitro and in vivo generation of procoagulant activity (tissue factor) by mononuclear phagocytes after intralipid infusion in rabbits. Blood 65:1391–5.PubMedGoogle Scholar
  9. 9.
    Semeraro N, Triggiani R, Montemurro P, Cavallo LG, Colucci M. (1993) Enhanced endothelial tissue factor but normal thrombomodulin in endotoxin-treated rabbits. Thromb. Res. 71:479–86.CrossRefGoogle Scholar
  10. 10.
    Broze GJ. (1995) Tissue factor pathway inhibitor and the revised theory of coagulation. Ann. Rev. Med. 46:103–12.CrossRefGoogle Scholar
  11. 11.
    Rao LVM. (1992) Tissue factor as a tumor procoagulant. Cancer Metastasis Rev. 11:249–66.CrossRefGoogle Scholar
  12. 12.
    Rickles FR, Hair GA, Zeff RA, Lee E, Bona RD. (1995) Tissue factor expression in human leukocytes and tumor cells. Thromb. Haemost. 74:391–5PubMedGoogle Scholar
  13. 13.
    Mueller BM, Reisfeld RA, Edgington TS, Ruf W. (1992) Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. Proc. Natl. Acad. Sci. U.S.A. 89:11832–6.CrossRefGoogle Scholar
  14. 14.
    Hamada K et al. (1996) Expression of tissue factor correlates with grade of malignancy in human glioma. Cancer 77:1877–83.CrossRefGoogle Scholar
  15. 15.
    Zhou JN, Ljungdahl S, Shoshan MC, Swedenborg J, Linder S. (1998) Activation of tissue-factor gene expression in breast carcinoma cells by stimulation of the RAF-ERK signaling pathway. Mol. Carcinog. 21:234–43.CrossRefGoogle Scholar
  16. 16.
    Shigemori C et al. (1998) Tissue factor expression and metastatic potential of colorectal cancer. Thromb. Haemost. 80:894–8.CrossRefGoogle Scholar
  17. 17.
    Seto S et al. (2000) Tissue factor expression in human colorectal carcinoma: correlation with hepatic metastasis and impact on prognosis. Cancer 88:295–301.CrossRefGoogle Scholar
  18. 18.
    Mueller BM, Ruf W. (1998) Requirement for binding of catalytically active factor VIIa in tissue factor dependent experimental metastasis. J. Clin. Invest. 101: 1372–8.CrossRefGoogle Scholar
  19. 19.
    Bugge TH et al. (1996) Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation. Proc. Natl. Acad. Sci. U.S.A. 93:6258–61.CrossRefGoogle Scholar
  20. 20.
    Carmeliet P et al. (1996) Role of tissue factor in embryonic blood vessel development. Nature 383:73–5.CrossRefGoogle Scholar
  21. 21.
    Koomagi R, Volm M. (1998) Tissue-factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis. Int. J. Cancer 79:19–22.CrossRefGoogle Scholar
  22. 22.
    Abdulkadir SA et al. (2000) Tissue factor expression and angiogenesis in human prostate carcinoma. Hum Pathol. 31:443–7.CrossRefGoogle Scholar
  23. 23.
    Takano S, Tsuboi K, Tomono Y, Mitsui Y, Nose T. (2000) Tissue factor, osteopontin, alphavbeta3 integrin expression in microvasculature of gliomas associated with vascular endothelial growth factor expression. Br. J. Cancer 82:1967–73.CrossRefGoogle Scholar
  24. 24.
    Shoji M et al. (1998) Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer. Am. J. Pathol. 152:399–411.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Zhang Y et al. (1994) Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J. Clin. Invest. 94:1320–7.CrossRefGoogle Scholar
  26. 26.
    Hembrough TA et al. (2003) Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism. Cancer Res. 63:2997–3000.PubMedGoogle Scholar
  27. 27.
    Harlos K et al. (1994) Crystal structure of the extracellular region of human tissue factor. Nature 370:662–6.CrossRefGoogle Scholar
  28. 28.
    Muller YA, Ultsch MH, Kelley RF, de Vos AM. (1994) Structure of the extracellular domain of human tissue factor: location of the factor vlla binding site. Biochemistry 33:10864–70.CrossRefGoogle Scholar
  29. 29.
    Ott I, Fischer E, Miyagi Y, Mueller BM, Ruf W. (1998) A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280. J. Cell Biol. 140:1241–53.CrossRefGoogle Scholar
  30. 30.
    Abe K et al. (1999) Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc. Natl. Acad. Sci. U.S.A. 96:8663–8.CrossRefGoogle Scholar
  31. 31.
    Sørensen BB et al. (1999) Factor VIIa-induced p42/44 mitogen-activated protein kinase activation requires the proteolytic activity of Factor VIIa and is independent of the tissue factor cytoplasmic domain. J. Biol. Chem. 274:21349–54.CrossRefGoogle Scholar
  32. 32.
    Camerer E, Huang W, Coughlin SR. (2000) Tissue factor and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc. Natl. Acad. Sci. U.S.A. 97:5255–60.CrossRefGoogle Scholar
  33. 33.
    Petersen LC et al. (2000) Exclusion of known protease-activated receptors in factor VIIa-induced signal transduction. Thromb. Haemost. 83:571–6.CrossRefGoogle Scholar
  34. 34.
    Riewald M, Ruf W. (2001) Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor. Proc. Natl. Acad. Sci. U.S.A. 98:7742–7.CrossRefGoogle Scholar
  35. 35.
    Røttingen JA, Enden T, Camerer E, Iversen JG, Prydz H. (1995) Binding of human factor VIIa to tissue factor induces cytosolic Ca2+ signals in J82 cells, transfected Cos-1 cells, Madin Darby canine kidney cells and in human endothelial cells, induced to synthesize tissue factor. J. Biol. Chem. 270:4650–60.CrossRefGoogle Scholar
  36. 36.
    Camerer E, Røttingen JA, Iversen JG, Prydz H. (1996) Coagulation factors VII and X induce Ca2+ oscillations in Madin-Darby canine kidney cells only when proteolytically active. J. Biol. Chem. 271:29034–42.CrossRefGoogle Scholar
  37. 37.
    Cunningham MA, Romas P, Hutchinson P, Holdsworth SR, Tipping PG. (1999) Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages. Blood 94:3413–20.PubMedGoogle Scholar
  38. 38.
    Pendurthi UR, Alok D, Rao LV. (1997) Binding of factor VIIa to tissue factor induces alterations in gene expression in human fibroblast cells: upregulation of poly(A) polymerase. Proc. Natl. Acad. Sci. U.S.A. 94:12598–603.CrossRefGoogle Scholar
  39. 39.
    Masuda M, Nakamura S, Murakami T, Komiyama Y, Takahashi H. (1996) Association of tissue factor with a g chain homodimer of the IgE receptor type I in cultured human monocytes. Eur. J. Immunol. 26:2529–32.CrossRefGoogle Scholar
  40. 40.
    Poulsen LK et al. (1998) Signal transduction via the mitogen activated protein kinase pathway induced by binding of coagulation factor VIIa to tissue factor. J. Biol. Chem. 273:6228–32.CrossRefGoogle Scholar
  41. 41.
    Camerer E et al. (1999) Coagulation factors VIIa and Xa induce cell signaling leading to the upregulation of the egr-1 gene. J. Biol. Chem. 274:32225–33.CrossRefGoogle Scholar
  42. 42.
    Melis E et al. (2001) Targeted deletion of the cytosolic domain of tissue factor in mice does not affect development. Biochem. Biophys. Res. Commun. 286:580–6.CrossRefGoogle Scholar
  43. 43.
    Versteeg HH et al. (2000) Factor VIIa/tissue factor-induced signaling via activation of Src-like kinases, phosphatidylinositol 3-kinase, and Rac. J. Biol. Chem. 275:28750–6.CrossRefGoogle Scholar
  44. 44.
    Versteeg HH et al. (2003) Regulation of the p21Ras-MAP kinase pathway by factor VIIa. J. Thromb. Haemost. 1:1012–8.CrossRefGoogle Scholar
  45. 45.
    Herbert JM, de Prost D, Ollivier V, Melis E, Carmeliet P. (2001) Tissue factor is not involved in the mitogenic activity of factor VIIa. Biochem. Biophys. Res. Commun. 28:1074–7.CrossRefGoogle Scholar
  46. 46.
    Blanc-Brude OP, Chambers RC, Leoni P, Dik WA, Laurent GJ. (2001) Factor Xa is a fibroblast mitogen via binding to effector-cell protease receptor-1 and autocrine release of PDGF. Am. J. Physiol. Cell Physiol. 281:C681–9.CrossRefGoogle Scholar
  47. 47.
    Camerer E, Gjernes E, Wiiger M, Pringle S, Prydz H. (2000) Binding of factor VIIa to tissue factor on keratinocytes induces gene expression. J. Biol. Chem. 275:6580–5.CrossRefGoogle Scholar
  48. 48.
    Pendurthi UR, Allen KE, Ezban M, Rao LV. (2000) Factor VIIa and thrombin induce the expression of Cyr61 and connective tissue growth factor, extracellular matrix signaling proteins that could act as possible downstream mediators in factor VIIa x tissue factor-induced signal transduction. J. Biol. Chem. 275:14632–41.CrossRefGoogle Scholar
  49. 49.
    Versteeg HH et al. (2002) VIIa/tissue factor interaction results in a tissue factor cytoplasmic domain-independent activation of protein synthesis, p70, and p90 S6 kinase phosphorylation. J. Biol. Chem. 277:27065–72.CrossRefGoogle Scholar
  50. 50.
    Wang X, Gjernes E, Prydz H. (2002) Factor VIIa induces tissue factor-dependent up-regulation of interleukin-8 in a human keratinocyte line. J. Biol. Chem. 277:23620–6.CrossRefGoogle Scholar
  51. 51.
    Sørensen BB, Rao LV, Tornehave D, Gammeltoft S, Petersen LC. (2003) Antiapoptotic effect of coagulation factor VIIa. Blood. 102:1708–15.CrossRefGoogle Scholar
  52. 52.
    Versteeg HH, Spek CA, Richel DJ, Peppelenbosch MP. (2004) Coagulation factors VIIa and Xa inhibit apoptosis and anoikis. Oncogene 23:410–7.CrossRefGoogle Scholar
  53. 53.
    Randolph GJ, Luther T, Albrecht A, Magdolen V, Muller WA. (1998) Role of tissue factor in adhesion of mononuclear phagocytes to and trafficking through endothelium in vitro. Blood 92:4167–77.PubMedGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2004

Authors and Affiliations

  • Henri H. Versteeg
    • 1
  • C. Arnold Spek
    • 1
  • Maikel P. Peppelenbosch
    • 1
  • Dick J. Richel
    • 1
  1. 1.Laboratory for Experimental Internal MedicineAcademic Medical CenterAmsterdamThe Netherlands

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