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Thromb Haemost 2001; 86(05): 1210-1214
DOI: 10.1055/s-0037-1616053
Review Article
Schattauer GmbH

Role of Protease-activated Receptor 1 in Tumor Metastasis Promoted by Tissue Factor

Michael E. Bromberg
1   Yale University School of Medicine, Department of Internal Medicine, New Haven, CT, USA
,
Michelle A. Bailly
1   Yale University School of Medicine, Department of Internal Medicine, New Haven, CT, USA
,
William H. Konigsberg
2   Yale University, Department of Molecular Biophysics and Biochemistry, New Haven, CT, USA
› Author AffiliationsThis research received support from NCI grant K11-CA64205 (MEB), Junior Faculty Scholar Award from the American Society of Hematology (MEB) and U.S. Public Health Services Grant PO1-HL 29019 (WHK).
Further Information

Publication History

Received 17 April 2001

Accepted after revision 05 June 2001

Publication Date:
13 December 2017 (online)

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Summary

Tissue factor (TF) is a transmembrane glycoprotein that complexes with factor VIIa to initiate blood coagulation. We previously reported that expression of high levels of TF in a human melanoma cell line promotes metastasis. Both the cytoplasmic domain of TF and its extracellular domain complexed with factor VIIa are required for the meta-static effect. To further explore the mechanism of TF-mediated metastasis, we investigated the possibility that a protease-activated receptor (PAR) might play a role. For this purpose, we first determined the expression levels of the known PARs (PAR1-4) in a human melanoma cell line, SIT1, that has low endogenous levels of TF and low meta-static potential. We found negligible levels of all of the known PARs and transfection of this cell line with human TF cDNA did not alter expression of the known PARs. To study the possible role of PAR1 in TF-mediated metastasis, we prepared a panel of transfected cell lines with varying levels of TF and PAR1. Our studies show that TF promotes metastasis by a pathway that does not involve high expression of known PARs by tumor cells. In addition, while overexpression of PAR1 is insufficient to induce metastasis in cells with low TF expression, it enhances the metastatic potential of cells with high TF expression, indicating a possible synergy between TF and PAR1 in promoting metastasis.

Keywords

Tissue factor - protease-activated receptor - factor VIIa - metastasis - melanoma
 

  • References

  • 1 Nemerson Y. Tissue factor and hemostasis. Blood 1988; 71: 1-8.
    PubMedGoogle Scholar
  • 2 Zhang Y, Deng Y, Luther T, Muller M, Ziegler R, Waldherr R, Stern DM, Nawroth PP. Tissue factor controls the balance of angiogenic and anti-angiogenic properties of tumor cells in mice. J Clin Invest 1994; 94: 1320-7.
    CrossrefPubMedGoogle Scholar
  • 3 Bromberg ME, Konigsberg WH, Madison JF, Pawashe A, Garen A. Tissue factor promotes metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci USA 1995; 92: 8205-9.
    CrossrefPubMedGoogle Scholar
  • 4 Mueller BM, Reisfield RA, Edgington T, Ruf W. Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. Proc Natl Acad Sci USA 1992; 89: 11832-6.
    CrossrefPubMedGoogle Scholar
  • 5 Abe K, Shoji M, Chen J, Bierhaus A, Danave I, Micko C, Casper K, Dillehay DL, Nawroth PP, Rickles FR. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc Natl Acad Sci USA 1999; 96: 8663-8.
    CrossrefPubMedGoogle Scholar
  • 6 Bromberg ME, Sundaram R, Homer RJ, Garen A, Konigsberg WH. Role of tissue factor in metastasis: function of the cytoplasmic and extracellular domains of the molecule. Thromb Haemost 1999; 82: 88-92.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Mueller BM, Ruf W. Requirement for binding of catalytically active factor VIIa in tissue factor-dependent experimental metastasis. J Clin Invest 1998; 101: 1372-8.
    CrossrefPubMedGoogle Scholar
  • 8 Fischer EG, Ruf W, Mueller BM. Tissue factor-initiated thrombin generation activates the thrombin receptor on malignant melanoma cells. Cancer Res 1995; 55: 1629-32.
    PubMedGoogle Scholar
  • 9 Nierodzik ML, Klepfish A, Karpatkin S. Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and Von Willebrand factor on tumor adhesion in vitro and metastasis in vivo . Thromb Haemost 1995; 74: 282-90.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Nierodzik ML, Chen K, Takeshita K, Li JJ, Huang YQ, Feng XS, D’Andrea MR, Andrade-Gordon P, Karpatkin S. Protease-activated receptor-1 (PAR-1) is required and rate limiting for thrombin-enhanced experimental pulmonary metastasis. Blood 1998; 92: 3694-700.
    PubMedGoogle Scholar
  • 11 Esumi N, Fan D, Fidler IJ. Inhibition of murine melanoma experimental metastasis by recombinant disulfatohirudin, a highly specific thrombin inhibitor. Cancer Res 1991; 51: 4549-56.
    PubMedGoogle Scholar
  • 12 Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258-64.
    CrossrefPubMedGoogle Scholar
  • 13 Wojtukiewicz MZ, Tang DG, Ben-Josef E. Solid tumor cells express functional “tethered ligand” thrombin receptor. Cancer Res 1995; 55: 698-704.
    PubMedGoogle Scholar
  • 14 Nierodzik MLR, Bain RM, Lin LX. Presence of the seven transmembrane thrombin receptor on human tumour cells: effect of activation on tumour adhesion to platelets and tumour tyrosine phosphorylation. Br J Haematology 1996; 92: 452-7.
    CrossrefPubMedGoogle Scholar
  • 15 Miyata S, Koshikawa N, Yasumitsu H, Miyazaki K. Trypsin stimulates integrin αβ-dependent adhesion to fibronectin and proliferation of gastric carcinoma cells through activation of proteinase-activated receptor-2. J Biol Chem 2000; 275: 4592-8.
    CrossrefPubMedGoogle Scholar
  • 16 Boehm S, Kong W, Broemme D, Smeekens SP, Anderson DC, Connolly A, Kahn M, Nelken N, Coughlin SR, Payan DG, Bunnett NW. Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. Biochem J 1996; 314: 1009-16.
    CrossrefPubMedGoogle Scholar
  • 17 Even-Ram S, Uziely B, Cohon P. Thrombin receptor overexpression in malignant and physiological invasion processes. Nature Med 1998; 4: 909-14.
    CrossrefPubMedGoogle Scholar
  • 18 Henrikson KP, Salazar SL, Fenton II JW, Pentecost BT. Role of thrombin receptor in breast cancer invasiveness. Br J Cancer 1999; 79: 401-6.
    CrossrefPubMedGoogle Scholar
  • 19 Camerer E, Rottingen JA, Iversen JG, Prydz H. Coagulation factor VII and coagulation factor X induce Ca2+ oscillations in Madin-Darby canine kidney cells only when proteolytically active. J Biol Chem 1996; 271: 29034-42.
    CrossrefPubMedGoogle Scholar
  • 20 Sorensen BB, Fresgarkgard PO, Nielson LS, Rao LVM, Ezban M, Petersen LC. Factor VIIa-induced p44/42 mitogen-activated protein kinase activation requires the proteolytic activity of factor VIIa and is independent of the tissue factor cytoplasmic domain. J Biol Chem 1999; 274: 21349-54.
    CrossrefPubMedGoogle Scholar
  • 21 Camerer E, Rottingen J-A, Gjernes E, Larsen K, Skartlien AH, Iversen J-G, Prydz H. Coagulation factors VIIa and Xa induce cell signaling leading to up-regulation of the egr-1 gene. J Biol Chem 1999; 274: 32225-33.
    CrossrefPubMedGoogle Scholar
  • 22 Pendurthi UR, Allen KE, Ezban M, Rao LVM. 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-tissue factor-induced signal transduction. J Biol Chem 2000; 275: 14632-41.
    CrossrefPubMedGoogle Scholar
  • 23 Peterson LC, Thastrup O, Hagel G, Sorensen BB, Feskgard P-O, Rao LVM, Ezban M. Exclusion of known protease activated receptors in factor VIIa-induced signal transduction. Thromb Haemost 2000; 83: 571-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Camerer E, Huang W, Coughlin SR. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci USA 2000; 97: 5255-60.
    CrossrefPubMedGoogle Scholar
  • 25 Ruf W, Mueller BM. Tissue factor signaling. Thromb Haemost 1999; 82: 175-82.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Morgenstern JP, Land H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug section markers and a complementary helper-free packaging cell line. Nucleic Acids Research 1990; 18: 3587-96.
    CrossrefPubMedGoogle Scholar
  • 27 Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR. Proteinase-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest 1999; 103: 879-87.
    CrossrefPubMedGoogle Scholar
  • 28 O’Brien PJ, Prevost N, Molino M, Holliger MK, Woolkalis MJ, Woulfe DS, Brass LF. Thrombin responses in human endothelial cells. J Biol Chem 2000; 275: 13502-9.
    CrossrefPubMedGoogle Scholar
  • 29 Hung DT, Wong YH, Vu TK, Coughlin SR. The cloned platelet thrombin receptor couples to at least two distinct effectors to stimulate phosphoinositide hydrolysis and inhibit adenylyl cyclase. J Biol Chem 1992; 267: 20831-4.
    PubMedGoogle Scholar
  • 30 Zioncheck TF, Roy S, Behar GA. The cytoplasmic domain of tissue factor is phosphorylated by a protein kinase C-dependent mechanism. J Biol Chem 1992; 267: 3561-4.
    PubMedGoogle Scholar
  • 31 Ott I, Fischer EG, Miyagi Y, Mueller BM, Ruf W. A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280. J Cell Bio 1998; 140: 1241-53.
    CrossrefPubMedGoogle Scholar