Tissue Factor and Protease-Activated Receptor Signaling in Cancer

 

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ABSTRACT

The activation of the coagulation cascade in the tumor microenvironment is a key feature of advanced malignancies. On tumor cells, tissue factor (TF) plays a central role to initiate cross-talk through the release of procoagulant microparticles or through direct, protease-activated receptor (PAR)-mediated cell signaling that leads to the production of soluble cytokines and angiogenic growth factors. In addition, the hemostatic system in the host compartment sustains crucial circuits that promote metastasis and support tumor growth and angiogenesis. Experimental tumor and genetic models have defined specific pathways that are supported by tumor cell and host TF and have identified potential therapeutic modalities to specifically interrupt TF signaling in tumor biology without impairment of hemostatic functions.

REFERENCES

• 1 Rickles F R, Patierno S, Fernandez P M. Tissue factor, thrombin, and cancer.  Chest. 2003;  124(3 Suppl) 58S-68S
  CrossrefPubMedGoogle Scholar
• 2 Clauss M, Gerlach M, Gerlach H et al.. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration.  J Exp Med. 1990;  172 1535-1545
  CrossrefPubMedGoogle Scholar
• 3 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
• 4 Ruf W, Mueller B M. Thrombin generation and the pathogenesis of cancer.  Semin Thromb Hemost. 2006;  32(Suppl 1) 61-68
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 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
• 6 Dvorak H F, Quay S C, Orenstein N S et al.. Tumor shedding and coagulation.  Science. 1981;  212 923-924
  CrossrefPubMedGoogle Scholar
• 7 Hron G, Kollars M, Weber H et al.. Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer.  Thromb Haemost. 2007;  97 119-123
  Google Scholar
• 8 Varki A. Trousseau's syndrome: multiple definitions and multiple mechanisms.  Blood. 2007;  110 1723-1729
  CrossrefPubMedGoogle Scholar
• 9 Chand H S, Ness S A, Kisiel W. Identification of a novel human tissue factor splice variant that is upregulated in tumor cells.  Int J Cancer. 2006;  118 1713-1720
  CrossrefPubMedGoogle Scholar
• 10 Bogdanov V Y, Balasubramanian V, Hathcock J, Vele O, Lieb M, Nemerson Y. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein.  Nat Med. 2003;  9 458-462
  Google Scholar
• 11 Bogdanov V Y, Kirk R I, Miller C et al.. Identification and characterization of murine alternatively spliced tissue factor.  J Thromb Haemost. 2006;  4 158-167
  PubMedGoogle Scholar
• 12 Yu J L, Rak J W. Shedding of tissue factor (TF)-containing microparticles rather than alternatively spliced TF is the main source of TF activity released from human cancer cells.  J Thromb Haemost. 2004;  2 2065-2067
  Google Scholar
• 13 Grimstad I A, Prydz H. Thromboplastin release,but not content,correlates with spontaneous metastasis of cancer cells.  Int J Cancer. 1988;  41 427-431
  CrossrefPubMedGoogle Scholar
• 14 Milsom C, Anderson G M, Weitz J I, Rak J. Elevated tissue factor procoagulant activity in CD133-positive cancer cells.  J Thromb Haemost. 2007;  5 2550-2552
  CrossrefPubMedGoogle Scholar
• 15 Sahni A, Simpson-Haidaris P J, Sahni S K, Vaday G G, Francis C W. Fibrinogen synthesized by cancer cells augments the proliferative effect of fibroblast growth factor-2 (FGF-2).  J Thromb Haemost. 2008;  6 176-183
  PubMedGoogle Scholar
• 16 Coughlin S R. Thrombin signalling and protease-activated receptors.  Nature. 2000;  407 258-264
  CrossrefPubMedGoogle Scholar
• 17 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
• 18 Smadja D M, Bieche I, Uzan G et al.. PAR-1 activation on human late endothelial progenitor cells enhances angiogenesis in vitro with upregulation of the SDF-1/CXCR4 system.  Arterioscler Thromb Vasc Biol. 2005;  25 2321-2327
  CrossrefPubMedGoogle Scholar
• 19 Kisucka J, Butterfield C E, Duda D G et al.. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage.  Proc Natl Acad Sci U S A. 2006;  103 855-860
  CrossrefPubMedGoogle Scholar
• 20 Camerer E, Qazi A A, Duong D N, Cornelissen I, Advincula R, Coughlin S R. Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis.  Blood. 2004;  104 397-401
  CrossrefPubMedGoogle Scholar
• 21 Rao L V, Pendurthi U R. Tissue factor-factor VIIa signaling.  Arterioscler Thromb Vasc Biol. 2005;  25 47-56
  PubMedGoogle Scholar
• 22 Belting M, Ahamed J, Ruf W. Signaling of the tissue factor coagulation pathway in angiogenesis and cancer.  Arterioscler Thromb Vasc Biol. 2005;  25 1545-1550
  CrossrefPubMedGoogle Scholar
• 23 Ahamed J, Versteeg H H, Kerver M et al.. Disulfide isomerization switches tissue factor from coagulation to cell signaling.  Proc Natl Acad Sci U S A. 2006;  103 13932-13937
  Google Scholar
• 24 Mueller B M, Reisfeld R A, Edgington T S, Ruf W. Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis.  Proc Natl Acad Sci U S A. 1992;  89 11832-11836
  PubMedGoogle Scholar
• 25 Nierodzik M L, Karpatkin S. Thrombin induces tumor growth, metastasis, and angiogenesis: evidence for a thrombin-regulated dormant tumor phenotype.  Cancer Cell. 2006;  10 355-362
  CrossrefPubMedGoogle Scholar
• 26 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
• 27 Bromberg M E, Konigsberg W H, Madison J F, Pawashe A, Garen A. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation.  Proc Natl Acad Sci U S A. 1995;  92 8205-8209
  Google Scholar
• 28 Palumbo J S, Talmage K E, Massari J V et al.. Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and -independent mechanisms.  Blood. 2007;  110 133-141
  CrossrefPubMedGoogle Scholar
• 29 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
• 30 Radjabi A R, Sawada K, Jagadeeswaran S et al.. Thrombin induces tumor invasion through the induction and association of matrix metalloproteinase-9 and {beta}1-integrin on the cell surface.  J Biol Chem. 2008;  283 2822-2834
  PubMedGoogle Scholar
• 31 Shi X, Gangadharan B, Brass L F, Ruf W, Mueller B M. Protease-activated receptor 1 (PAR1) and PAR2 contribute to tumor cell motility and metastasis.  Mol Cancer Res. 2004;  2 395-402
  PubMedGoogle Scholar
• 32 Camerer E, Duong D N, Hamilton J R, Coughlin S R. Combined deficiency of protease-activated receptor-4 and fibrinogen recapitulates the hemostatic defect but not the embryonic lethality of prothrombin deficiency.  Blood. 2004;  103 152-154
  CrossrefPubMedGoogle Scholar
• 33 Dorfleutner A, Hintermann E, Tarui T, Takada Y, Ruf W. Crosstalk of integrin α3β1 and tissue factor in cell migration.  Mol Biol Cell. 2004;  15 4416-4425
  CrossrefPubMedGoogle Scholar
• 34 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
• 35 Ott I, Weigand B, Michl R et al.. Tissue factor cytoplasmic domain stimulates migration by activation of the GTPase Rac1 and the mitogen-activated protein kinase p38.  Circulation. 2005;  111 349-355
  CrossrefPubMedGoogle Scholar
• 36 Ahamed J, Niessen F, Kurokawa T et al.. Regulation of macrophage procoagulant responses by the tissue factor cytoplasmic domain in endotoxemia.  Blood. 2007;  109 5251-5259
  CrossrefPubMedGoogle Scholar
• 37 Siegbahn A, Johnell M, Sørensen B B, Petersen L C, Heldin C H. Regulation of chemotaxis by the cytoplasmic domain of tissue factor.  Thromb Haemost. 2005;  93 27-34
  PubMedGoogle Scholar
• 38 Versteeg H H, Schaffner F, Kerver M et al.. Inhibition of tissue factor signaling suppresses tumor growth.  Blood. 2008;  111 190-199
  CrossrefPubMedGoogle Scholar
• 39 Ruf W, Dorfleutner A, Riewald M. Specificity of coagulation factor signaling.  J Thromb Haemost. 2003;  1 1495-1503
  CrossrefPubMedGoogle Scholar
• 40 Morris D R, Ding Y, Ricks T K, Gullapalli A, Wolfe B L, Trejo J. Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells.  Cancer Res. 2006;  66 307-314
  CrossrefPubMedGoogle Scholar
• 41 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 via PAR-2 and results in increased cell migration.  Blood. 2004;  103 3029-3037
  Google Scholar
• 42 Zoudilova M, Kumar P, Ge L, Wang P, Bokoch G M, DeFea K A. Beta-arrestin-dependent regulation of the cofilin pathway downstream of protease-activated receptor-2.  J Biol Chem. 2007;  282 20634-20646
  CrossrefPubMedGoogle Scholar
• 43 Koizume S, Jin M-S, Miyagi E et al.. Activation of cancer cell migration and invasion by ectopic synthesis of coagulation factor VII.  Cancer Res. 2006;  66 9453-9460
  CrossrefPubMedGoogle Scholar
• 44 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
• 45 Sorensen B B, Rao L VM, Tornehave D, Gammeltoft S, Petersen L C. Anti-apoptotic effect of coagulation factor VIIa.  Blood. 2003;  102 1708-1715
  CrossrefPubMedGoogle Scholar
• 46 Versteeg H H, Arnold S C, Richel D J, Peppelenbosch M P. Coagulation factors VIIa and Xa inhibit apoptosis and anoikis.  Oncogene. 2004;  23 410-417
  CrossrefPubMedGoogle Scholar
• 47 Pendurthi U R, Allen K E, Ezban M, Rao L VM. 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 14632-14641
  CrossrefPubMedGoogle Scholar
• 48 Camerer E, Gjernes E, Wiiger M, Pringle S, Prydz H. Binding of factor VIIa to tissue factor on keratinocytes induces gene expression.  J Biol Chem. 2000;  275 6580-6585
  CrossrefPubMedGoogle Scholar
• 49 Liu Y, Mueller B M. Protease-activated receptor-2 regulates vascular endothelial growth factor expression in MDA-MB-231 cells via MAPK pathways.  Biochem Biophys Res Commun. 2006;  344 1263-1270
  CrossrefPubMedGoogle Scholar
• 50 Albrektsen T, Sorensen B B, Hjortoe G M, Fleckner J, Rao L VM, Petersen L C. Transcriptional program induced by factor VIIa-tissue factor, PAR1 and PAR2 in MDA-MB-231 cells.  J Thromb Haemost. 2007;  5 1588-1597
  CrossrefPubMedGoogle Scholar
• 51 Uusitalo-Jarvinen H, Kurokawa T, Mueller B M, Andrade-Gordon P, Friedlander M, Ruf W. Role of protease activated receptor 1 and 2 signaling in hypoxia-induced angiogenesis.  Arterioscler Thromb Vasc Biol. 2007;  27 1456-1462
  CrossrefPubMedGoogle Scholar
• 52 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
• 53 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
• 54 Griffin C T, Srinavasan 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
• 55 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
• 56 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
• 57 Zania P, Kritikou S, Flordellis C S, Maragoudakis M E, Tsopanoglou N E. Blockade of angiogenesis by small molecule antagonists to protease-activated receptor-1 (PAR-1): association with endothelial cell growth suppression and induction of apoptosis.  J Pharmacol Exp Ther. 2006;  318 246-254
  CrossrefPubMedGoogle Scholar
• 58 Colognato R, Slupsky J R, Jendrach M, Burysek L, Syrovets T, Simmet T. Differential expression and regulation of protease-activated receptors in human peripheral monocytes and monocyte-derived antigen-presenting cells.  Blood. 2003;  102 2645-2652
  CrossrefPubMedGoogle Scholar
• 59 Fields R C, Schoenecker J G, Hart J P, Hoffman M R, Pizzo S V, Lawson J H. Protease-activated receptor-2 signaling triggers dendritic cell development.  Am J Pathol. 2003;  162 1817-1822
  PubMedGoogle Scholar
• 60 Csernok E, Ai M, Gross W L et al.. Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway.  Blood. 2006;  107 4440-4448
  CrossrefPubMedGoogle Scholar
• 61 Rafii D C, Psaila B, Butler J, Jin D K, Lyden D. Regulation of vasculogenesis by platelet-mediated recruitment of bone marrow-derived cells.  Arterioscler Thromb Vasc Biol. 2008;  28 217-222
  CrossrefPubMedGoogle Scholar
• 62 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
• 63 Kakkar A K, Chinswangwatanakul V, Lemoine N R, Tebbutt S, Williamson R CN. Role of tissue factor expression on tumour cell invasion and growth of experimental pancreatic adenocarcinoma.  Br J Surg. 1999;  86 890-894
  CrossrefPubMedGoogle Scholar
• 64 Abe K, Shoji M, Chen J et al.. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor.  Proc Natl Acad Sci U S A. 1999;  96 8663-8668
  Google Scholar
• 65 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
• 66 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
• 67 Martin C B, Mahon G, Klinger M et al.. The thrombin receptor, PAR-1, causes transformation by activation of Rho-mediated signaling pathways.  Oncogene. 2001;  20 1953-1963
  CrossrefPubMedGoogle Scholar
• 68 Yin Y J, Katz V, Salah Z et al.. Mammary gland tissue targeted overexpression of human protease-activated receptor 1 reveals a novel link to beta-catenin stabilization.  Cancer Res. 2006;  66 5224-5233
  CrossrefPubMedGoogle Scholar
• 69 Gupta G P, Nguyen D X, Chiang A C et al.. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis.  Nature. 2007;  446 765-770
  CrossrefPubMedGoogle Scholar
• 70 Caunt M, Hu L, Tang T, Brooks P C, Ibrahim S, Karpatkin S. Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis.  Cancer Res. 2006;  66 4125-4132
  CrossrefPubMedGoogle Scholar
• 71 Miller G J, Bauer K A, Howarth D J, Cooper J A, Humphries S E, Rosenberg R D. Increased incidence of neoplasia of the digestive tract in men with persistent activation of the coagulant pathway.  J Thromb Haemost. 2004;  2 2107-2114
  CrossrefPubMedGoogle Scholar
• 72 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.  Cancer. 1984;  53 2046-2052
  CrossrefPubMedGoogle Scholar
• 73 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
• 74 Kakkar A K, Levine M N, Kadziola Z et al.. Low molecular weight heparin. therapy with dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study (FAMOUS).  J Clin Oncol. 2004;  22 1944-1948
  CrossrefPubMedGoogle Scholar
• 75 Lee A YY, Rickles F R, Julian J A et al.. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism.  J Clin Oncol. 2005;  23 2123-2129
  Google Scholar
• 76 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

Wolfram RufM.D. 

Department of Immunology, SP258, The Scripps Research Institute

10550 North Torrey Pines Road, La Jolla, CA 92037

Email: ruf@scripps.edu