Download PDF
Semin Thromb Hemost 2006; 32: 061-068
DOI: 10.1055/s-2006-939555
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Thrombin Generation and the Pathogenesis of Cancer

Wolfram Ruf1 , Barbara M. Mueller1
  • 1Scripps Research Institute and the La Jolla Institute for Molecular Medicine, San Diego, California
Further Information

Publication History

Publication Date:
02 May 2006 (online)

    Permissions and Reprints

ABSTRACT

Advanced cancer is associated with a hypercoagulable state that is triggered by tissue factor (TF). TF-initiated thrombin generation is crucial for metastasis through fibrin and platelet deposition, as well as thrombin-dependent protease-activated receptor (PAR) 1 signaling. Surprisingly, PAR2, which is not cleaved by thrombin, appears to cosignal with PAR1 to elicit thrombin effects in metastatic tumor cells. In contrast to TF-driven thrombin pathways in metastasis, direct TF signaling plays a role in angiogenesis-dependent tumor growth. In TF cytoplasmic-domain-deleted mice, PAR2-dependent angiogenesis and tumor growth is enhanced, demonstrating a role for host cell TF signaling. In tumor cells, TF-factor VIIa (FVIIa) activates PAR2 and thereby regulates proangiogenic growth factor expression as well as integrins involving crosstalk with the TF cytoplasmic domain. In addition to thrombin-PAR signaling in metastasis and TF-FVIIa-PAR2 signaling in tumor growth, it is likely that additional protease pathways will prove to be crucial activators of PARs in cancer. Transmembrane serine proteases as well as matrix metalloproteinase are prime candidates for accessory pathways to regulate metastasis, tumor expansion, and angiogenesis dependent on specific features of the local tumor microenvironment.

KEYWORDS

Tissue factor - protease activated receptors - protease signaling - metastasis - angiogenesis

REFERENCES

  • 1 Rickles F R, Patierno S, Fernandez P M. Tissue factor, thrombin, and cancer.  Chest. 2003;  124 58S-68S
    CrossrefPubMedGoogle Scholar
  • 2 Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. Duration of Anticoagulation Trial.  N Engl J Med. 2000;  342 1953-1958
    CrossrefPubMedGoogle Scholar
  • 3 Klerk C P, Smorenburg S M, Otten H M et al.. The effect of low molecular weight heparin on survival in patients with advanced malignancy.  J Clin Oncol. 2005;  23 2130-2135
    CrossrefPubMedGoogle Scholar
  • 4 Coughlin S R. Thrombin signalling and protease-activated receptors.  Nature. 2000;  407 258-264
    CrossrefPubMedGoogle Scholar
  • 5 Yin Y J, Salah Z, Grisaru-Granovsky S et al.. Human protease-activated receptor 1 expression in malignant epithelia: a role in invasiveness.  Arterioscler Thromb Vasc Biol. 2003;  23 940-944
    PubMedGoogle Scholar
  • 6 Booden M A, Eckert L B, Der C J, Trejo J. Persistent signaling by dysregulated thrombin receptor trafficking promotes breast carcinoma cell invasion.  Mol Cell Biol. 2004;  24 1990-1999
    CrossrefPubMedGoogle Scholar
  • 7 Fischer E G, Ruf W, Mueller B M. Tissue factor-initiated thrombin generation activates the signaling thrombin receptor on malignant melanoma cells.  Cancer Res. 1995;  55 1629-1632
    PubMedGoogle Scholar
  • 8 Massi D, Naldini A, Ardinghi C et al.. Expression of protease-activated receptors 1 and 2 in melanocytic nevi and malignant melanoma.  Hum Pathol. 2005;  36 676-685
    CrossrefPubMedGoogle Scholar
  • 9 Chay C H, Cooper C R, Gendernalik J D et al.. A functional thrombin receptor (PAR1) is expressed on bone-derived prostate cancer cell lines.  Urology. 2002;  60 760-765
    CrossrefPubMedGoogle Scholar
  • 10 Miyata S, Koshikawa N, Yasumitsu H, Miyazaki K. Trypsin stimulates integrin alpha(5)beta(1)-dependent adhesion to fibronectin and proliferation of human gastric carcinoma cells through activation of proteinase-activated receptor-2.  J Biol Chem. 2000;  275 4592-4598
    CrossrefPubMedGoogle Scholar
  • 11 Ge L, Shenoy S K, Lefkowitz R J, DeFea K. Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and -2.  J Biol Chem. 2004;  279 55419-55424
    CrossrefPubMedGoogle Scholar
  • 12 Hjortoe G M, Petersen L C, Albrektsen T et al.. Tissue factor-factor VIIa-specific up-regulation of IL-8 expression in MDA-MB-231 cells is mediated by PAR-2 and results in increased cell migration.  Blood. 2004;  103 3029-3037
    Google Scholar
  • 13 D'Andrea M R, Derian C K, Santulli R J, Andrade-Gordon P. Differential expression of protease-activated receptors-1 and -2 in stromal fibroblasts of normal, benign, and malignant human tissues.  Am J Pathol. 2001;  158 2031-2041
    PubMedGoogle Scholar
  • 14 Riewald M, Ruf W. Protease-activated receptor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling.  J Biol Chem. 2005;  280 19808-19814
    CrossrefPubMedGoogle Scholar
  • 15 Boire A, Covic L, Agarwal A et al.. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells.  Cell. 2005;  120 303-313
    CrossrefPubMedGoogle Scholar
  • 16 Kamath L, Meydani A, Foss F, Kuliopulos A. Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells.  Cancer Res. 2001;  61 5933-5940
    PubMedGoogle Scholar
  • 17 Ruf W, Dorfleutner A, Riewald M. Specificity of coagulation factor signaling.  J Thromb Haemost. 2003;  1 1495-1503
    CrossrefPubMedGoogle Scholar
  • 18 Camerer E, Huang W, Coughlin S R. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa.  Proc Natl Acad Sci USA. 2000;  97 5255-5260
    CrossrefPubMedGoogle Scholar
  • 19 Riewald M, Ruf W. Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor.  Proc Natl Acad Sci USA. 2001;  98 7742-7747
    CrossrefPubMedGoogle Scholar
  • 20 Riewald M, Kravchenko V V, Petrovan R J et al.. Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1.  Blood. 2001;  97 3109-3116
    Google Scholar
  • 21 Ahamed J, Belting M, Ruf W. Regulation of tissue factor-induced signaling by endogenous and recombinant tissue factor pathway inhibitor 1.  Blood. 2005;  105 2384-2391
    Google Scholar
  • 22 Esumi N, Fan D, Fidler I J. Inhibition of murine melanoma experimental metastasis by recombinant desulfatohirudin, a highly specific thrombin inhibitor.  Cancer Res. 1991;  51 4549-4556
    PubMedGoogle Scholar
  • 23 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. 1992;  89 11832-11836
    PubMedGoogle Scholar
  • 24 Im J H, Fu W, Wang H et al.. Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation.  Cancer Res. 2004;  64 8613-8619
    CrossrefPubMedGoogle Scholar
  • 25 Ruf W, Mueller B M. Tissue factor in cancer angiogenesis and metastasis.  Curr Opin Hematol. 1996;  3 379-384
    CrossrefPubMedGoogle Scholar
  • 26 Vogel S M, Gao X, Mehta D et al.. Abrogation of thrombin-induced increase in pulmonary microvascular permeability in PAR-1 knockout mice.  Physiol Genomics. 2000;  4 137-145
    PubMedGoogle Scholar
  • 27 Wang H, Fu W, Im J H et al.. Tumor cell alpha3beta1 integrin and vascular laminin-5 mediate pulmonary arrest and metastasis.  J Cell Biol. 2004;  164 935-941
    CrossrefPubMedGoogle Scholar
  • 28 Mueller B M, Ruf W. Requirement for binding of catalytically active factor VIIa in tissue factor-dependent experimental metastasis.  J Clin Invest. 1998;  101 1372-1378
    Google Scholar
  • 29 Bromberg M E, Sundaram R, Homer R J, Garen A, Konigsberg W H. Role of tissue factor in metastasis: functions of the cytoplasmic and extracellular domains of the molecule.  Thromb Haemost. 1999;  82 88-92
    PubMedGoogle Scholar
  • 30 Dorfleutner A, Hintermann E, Tarui T, Takada Y, Ruf W. Cross-talk of integrin alpha3beta1 and tissue factor in cell migration.  Mol Biol Cell. 2004;  15 4416-4425
    CrossrefPubMedGoogle Scholar
  • 31 Palumbo J S, Talmage K E, Massari J V et al.. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells.  Blood. 2005;  105 178-185
    CrossrefPubMedGoogle Scholar
  • 32 Camerer E, Qazi A A, Duong D N et al.. Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis.  Blood. 2004;  104 397-401
    CrossrefPubMedGoogle Scholar
  • 33 Boucharaba A, Serre C M, Gres S et al.. Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer.  J Clin Invest. 2004;  114 1714-1725
    CrossrefPubMedGoogle Scholar
  • 34 Nierodzik M L, Chen K, Takeshita K et al.. Protease-activated receptor 1 (PAR-1) is required and rate-limiting for thrombin-enhanced experimental pulmonary metastasis.  Blood. 1998;  92 3694-3700
    PubMedGoogle Scholar
  • 35 Fischer E G, Riewald M, Huang H Y et al.. Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor.  J Clin Invest. 1999;  104 1213-1221
    Google Scholar
  • 36 Karpatkin S. Does hypercoagulability awaken dormant tumor cells in the host?.  J Thromb Haemost. 2004;  2 2103-2106
    CrossrefPubMedGoogle Scholar
  • 37 Shi X, Gangadharan B, Brass L F, Ruf W, Mueller B M. Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis.  Mol Cancer Res. 2004;  2 395-402
    PubMedGoogle Scholar
  • 38 O'Brien P J, Prevost N, Molino M et al.. Thrombin responses in human endothelial cells. Contributions from receptors other than PAR1 include the transactivation of PAR2 by thrombin-cleaved PAR1.  J Biol Chem. 2000;  275 13502-13509
    CrossrefPubMedGoogle Scholar
  • 39 Hu L, Lee M, Campbell W, Perez-Soler R, Karpatkin S. Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis.  Blood. 2004;  104 2746-2751
    CrossrefPubMedGoogle Scholar
  • 40 Shoji M, Hancock W W, Abe K et al.. 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. 1998;  152 399-411
    PubMedGoogle Scholar
  • 41 Palumbo J S, Potter J M, Kaplan L S et al.. Spontaneous hematogenous and lymphatic metastasis, but not primary tumor growth or angiogenesis, is diminished in fibrinogen-deficient mice.  Cancer Res. 2002;  62 6966-6972
    PubMedGoogle Scholar
  • 42 Palumbo J S, Kombrinck K W, Drew A F et al.. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells.  Blood. 2000;  96 3302-3309
    Google Scholar
  • 43 Caunt M, Huang Y Q, Brooks P C, Karpatkin S. Thrombin induces neoangiogenesis in the chick chorioallantoic membrane.  J Thromb Haemost. 2003;  1 2097-2102
    CrossrefPubMedGoogle Scholar
  • 44 Haralabopoulos G C, Grant D S, Kleinman H K, Maragoudakis M E. Thrombin promotes endothelial cell alignment in Matrigel in vitro and angiogenesis in vivo.  Am J Physiol. 1997;  273 C239-C245
    PubMedGoogle Scholar
  • 45 Flynn A N, Buret A G. Proteinase-activated receptor 1 (PAR-1) and cell apoptosis.  Apoptosis. 2004;  9 729-737
    CrossrefPubMedGoogle Scholar
  • 46 Versteeg H H, Spek C A, Richel D J, Peppelenbosch M P. Coagulation factors VIIa and Xa inhibit apoptosis and anoikis.  Oncogene. 2004;  23 410-417
    CrossrefPubMedGoogle Scholar
  • 47 Sorensen B B, Rao L V, Tornehave D, Gammeltoft S, Petersen L C. Antiapoptotic effect of coagulation factor VIIa.  Blood. 2003;  102 1708-1715
    CrossrefPubMedGoogle Scholar
  • 48 Darmoul D, Gratio V, Devaud H, Laburthe M. Protease-activated receptor 2 in colon cancer: trypsin-induced MAPK phosphorylation and cell proliferation are mediated by epidermal growth factor receptor transactivation.  J Biol Chem. 2004;  279 20927-20934
    CrossrefPubMedGoogle Scholar
  • 49 Prenzel N, Zwick E, Daub H et al.. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF.  Nature. 1999;  402 884-888
    PubMedGoogle Scholar
  • 50 Wiiger M T, Prydz H. The epidermal growth factor receptor (EGFR) and proline rich tyrosine kinase 2 (PYK2) are involved in tissue factor dependent factor VIIa signalling in HaCaT cells.  Thromb Haemost. 2004;  92 13-22
    PubMedGoogle Scholar
  • 51 Wang X, Gjernes E, Prydz H. Factor VIIa induces tissue factor-dependent up-regulation of interleukin-8 in a human keratinocyte line.  J Biol Chem. 2002;  277 23620-23626
    CrossrefPubMedGoogle Scholar
  • 52 Zhang Y, Deng Y, Luther T et al.. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice.  J Clin Invest. 1994;  94 1320-1327
    Google Scholar
  • 53 Yu J L, May L, Lhotak V et al.. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis.  Blood. 2005;  105 1734-1741
    CrossrefPubMedGoogle Scholar
  • 54 Hembrough T A, Swartz G M, Papathanassiu A et al.. Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism.  Cancer Res. 2003;  63 2997-3000
    Google Scholar
  • 55 Belting M, Dorrell M I, Sandgren S et al.. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling.  Nat Med. 2004;  10 502-509
    Google Scholar
  • 56 Carmeliet P, Mackman N, Moons L et al.. Role of tissue factor in embryonic blood vessel development.  Nature. 1996;  383 73-75
    CrossrefPubMedGoogle Scholar
  • 57 Griffin C T, Srinivasan Y, Zheng Y W, Huang W, Coughlin S R. A role for thrombin receptor signaling in endothelial cells during embryonic development.  Science. 2001;  293 1666-1670
    CrossrefPubMedGoogle Scholar
  • 58 Contrino J, Hair G, Kreutzer D L, Rickles F R. In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease.  Nat Med. 1996;  2 209-215
    CrossrefPubMedGoogle Scholar
  • 59 Seo D W, Li H, Guedez L et al.. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism.  Cell. 2003;  114 171-180
    CrossrefPubMedGoogle Scholar
  • 60 Siegbahn A, Johnell M, Rorsman C et al.. Binding of factor VIIa to tissue factor on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis.  Blood. 2000;  96 3452-3458
    PubMedGoogle Scholar
  • 61 Ge L, Ly Y, Hollenberg M, DeFea K. A beta-arrestin-dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease-activated receptor-2-induced chemotaxis.  J Biol Chem. 2003;  278 34418-34426
    CrossrefPubMedGoogle Scholar
  • 62 Ahamed J, Ruf W. Protease-activated receptor 2-dependent phosphorylation of the tissue factor cytoplasmic domain.  J Biol Chem. 2004;  279 23038-23044
    Google Scholar
  • 63 Dorfleutner A, Ruf W. Regulation of tissue factor cytoplasmic domain phosphorylation by palmitoylation.  Blood. 2003;  102 3998-4005
    CrossrefPubMedGoogle Scholar
  • 64 Johnsen M, Lund L R, Romer J, Almholt K, Dano K. Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation.  Curr Opin Cell Biol. 1998;  10 667-671
    CrossrefPubMedGoogle Scholar
  • 65 Pendurthi U R, Ngyuen M, Andrade-Gordon P, Petersen L C, Rao L V. Plasmin induces Cyr61 gene expression in fibroblasts via protease-activated receptor-1 and p44/42 mitogen-activated protein kinase-dependent signaling pathway.  Arterioscler Thromb Vasc Biol. 2002;  22 1421-1426
    PubMedGoogle Scholar
  • 66 Majumdar M, Tarui T, Shi B et al.. Plasmin-induced migration requires signaling through protease-activated receptor 1 and integrin alpha(9)beta(1).  J Biol Chem. 2004;  279 37528-37534
    CrossrefPubMedGoogle Scholar
  • 67 Riewald M, Petrovan R J, Donner A, Mueller B M, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway.  Science. 2002;  296 1880-1882
    CrossrefPubMedGoogle Scholar
  • 68 Uchiba M, Okajima K, Oike Y et al.. Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo.  Circ Res. 2004;  95 34-41
    CrossrefPubMedGoogle Scholar
  • 69 Lourbakos A, Chinni C, Thompson P et al.. Cleavage and activation of proteinase-activated receptor-2 on human neutrophils by gingipain-R from Porphyromonas gingivalis .  FEBS Lett. 1998;  435 45-48
    CrossrefPubMedGoogle Scholar
  • 70 Smith R, Jenkins A, Lourbakos A et al.. Evidence for the activation of PAR-2 by the sperm protease, acrosin: expression of the receptor on oocytes.  FEBS Lett. 2000;  484 285-290
    CrossrefPubMedGoogle Scholar
  • 71 Molino M, Barnathan E S, Numerof R et al.. Interactions of mast cell tryptase with thrombin receptors and PAR-2.  J Biol Chem. 1997;  272 4043-4049
    CrossrefPubMedGoogle Scholar
  • 72 Wilson S, Greer B, Hooper J et al.. The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells.  Biochem J. 2005;  388 967-972
    CrossrefPubMedGoogle Scholar
  • 73 Takeuchi T, Harris J L, Huang W et al.. Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates.  J Biol Chem. 2000;  275 26333-26342
    CrossrefPubMedGoogle Scholar
  • 74 Galkin A V, Mullen L, Fox W D et al.. CVS-3983, a selective matriptase inhibitor, suppresses the growth of androgen independent prostate tumor xenografts.  Prostate. 2004;  61 228-235
    CrossrefPubMedGoogle Scholar
  • 75 Aimes R T, Zijlstra A, Hooper J D et al.. Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis.  Thromb Haemost. 2003;  89 561-572
    Article in Thieme ConnectPubMedGoogle Scholar
  • 76 Netzel-Arnett S, Hooper J D, Szabo R et al.. Membrane anchored serine proteases: a rapidly expanding group of cell surface proteolytic enzymes with potential roles in cancer.  Cancer Metastasis Rev. 2003;  22 237-258
    CrossrefPubMedGoogle Scholar
  • 77 Zacharski L R, Henderson W G, Rickles F R et al.. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75.  Cancer. 1984;  53 2046-2052
    CrossrefPubMedGoogle Scholar

Wolfram RufM.D. 

Department of Immunology

SP258, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037

Email: ruf@scripps.edu