Activation of blood coagulation in cancer: implications for tumour progression

Several studies have suggested a role for blood coagulation proteins in tumour progression. Herein, we discuss (1) the activation of the blood clotting cascade in the tumour microenvironment and its impact on primary tumour growth; (2) the intravascular activation of blood coagulation and its impact on tumour metastasis and cancer-associated thrombosis; and (3) antitumour therapies that target blood-coagulation-associated proteins. Expression levels of the clotting initiator protein TF (tissue factor) have been correlated with tumour cell aggressiveness. Simultaneous TF expression and PS (phosphatidylserine) exposure by tumour cells promote the extravascular activation of blood coagulation. The generation of blood coagulation enzymes in the tumour microenvironment may trigger the activation of PARs (protease-activated receptors). In particular, PAR1 and PAR2 have been associated with many aspects of tumour biology. The procoagulant activity of circulating tumour cells favours metastasis, whereas the release of TF-bearing MVs (microvesicles) into the circulation has been correlated with cancer-associated thrombosis. Given the role of coagulation proteins in tumour progression, it has been proposed that they could be targets for the development of new antitumour therapies.

[1]  W. Ruf,et al.  Tissue factor and cell signalling in cancer progression and thrombosis , 2011, Journal of thrombosis and haemostasis : JTH.

[2]  C. Bokemeyer,et al.  Experimental metastasis and primary tumor growth in mice with hemophilia A , 2006, Journal of thrombosis and haemostasis : JTH.

[3]  N. Bunnett,et al.  Protease-activated receptors: contribution to physiology and disease. , 2004, Physiological reviews.

[4]  Garth W. Tormoen,et al.  Do circulating tumor cells play a role in coagulation and thrombosis? , 2012, Front. Oncol..

[5]  W. Ruf,et al.  Tissue factor and protease-activated receptor signaling in cancer. , 2008, Seminars in thrombosis and hemostasis.

[6]  J. Ribeiro,et al.  Antithrombotic properties of Ixolaris, a potent inhibitor of the extrinsic pathway of the coagulation cascade , 2006, Thrombosis and Haemostasis.

[7]  F. Rickles,et al.  Activation of blood coagulation in cancer: Trousseau's syndrome revisited. , 1983, Blood.

[8]  A. Schroit,et al.  Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. , 1997, Blood.

[9]  Xiaofeng Jiang,et al.  Formation of tissue factor–factor VIIa–factor Xa complex promotes cellular signaling and migration of human breast cancer cells , 2004, Journal of thrombosis and haemostasis : JTH.

[10]  J. Rak,et al.  Shedding of tissue factor (TF)‐containing microparticles rather than alternatively spliced TF is the main source of TF activity released from human cancer cells , 2004, Journal of thrombosis and haemostasis : JTH.

[11]  J. Olsen,et al.  Prognosis of cancers associated with venous thromboembolism. , 2000, The New England journal of medicine.

[12]  R. Nieuwland,et al.  Cellular microparticles: new players in the field of vascular disease? , 2004, European journal of clinical investigation.

[13]  M. Bar‐eli,et al.  The Emerging Role of the Thrombin Receptor (PAR-1) in Melanoma Metastasis - a Possible Therapeutic Target , 2011, Oncotarget.

[14]  M. Barcinski,et al.  Malignant transformation in melanocytes is associated with increased production of procoagulant microvesicles , 2011, Thrombosis and Haemostasis.

[15]  B. Brenner,et al.  Microparticles, thrombosis and cancer. , 2009, Best practice & research. Clinical haematology.

[16]  V. Rumjanek,et al.  On the molecular mechanisms for the highly procoagulant pattern of C6 glioma cells , 2006, Journal of Thrombosis and Haemostasis.

[17]  A. Falanga,et al.  Molecular basis for the relationship between thrombosis and cancer. , 2001, Thrombosis research.

[18]  B. Pentecost,et al.  Role of thrombin receptor in breast cancer invasiveness , 1999, British Journal of Cancer.

[19]  F. Rodeghiero,et al.  Characterization of a novel bleeding disorder with isolated prolonged bleeding time and deficiency of platelet microvesicle generation , 1997, British journal of haematology.

[20]  Flor A. Cianchetti,et al.  Development of Coagulation Factor Probes for the Identification of Procoagulant Circulating Tumor Cells , 2012, Front. Oncol..

[21]  D. Neuberg,et al.  Tumor-Derived Tissue FactorBearing Microparticles Are Associated With Venous Thromboembolic Events in Malignancy , 2009, Clinical Cancer Research.

[22]  P. Nawroth,et al.  Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M E Maragoudakis,et al.  Effects of thrombin/thrombosis in angiogenesis and tumour progression. , 2000, Matrix biology : journal of the International Society for Matrix Biology.

[24]  T. Peretz,et al.  Human protease-activated receptor 1 expression in malignant epithelia: a role in invasiveness. , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[25]  J. Colon,et al.  Tissue factor‐bearing microparticles derived from tumor cells: impact on coagulation activation , 2008, Journal of thrombosis and haemostasis : JTH.

[26]  S. Park,et al.  Galectin-3 Facilitates Cell Motility in Gastric Cancer by Up-Regulating Protease-Activated Receptor-1(PAR-1) and Matrix Metalloproteinase-1(MMP-1) , 2011, PloS one.

[27]  Haijun Yu,et al.  MicroRNA-19 (miR-19) Regulates Tissue Factor Expression in Breast Cancer Cells* , 2010, The Journal of Biological Chemistry.

[28]  Anna Janowska-Wieczorek,et al.  Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer , 2005, International journal of cancer.

[29]  K. Takeshita,et al.  Protease-activated receptor 1 (PAR-1) is required and rate-limiting for thrombin-enhanced experimental pulmonary metastasis. , 1998, Blood.

[30]  L. Lacombe,et al.  Tissue factor expression correlates with disease‐specific survival in patients with node‐negative muscle‐invasive bladder cancer , 2007, International journal of cancer.

[31]  J. Bernaudin,et al.  Tissue factor over-expression by human pancreatic cancer cells BXPC3 is related to higher prothrombotic potential as compared to breast cancer cells MCF7. , 2012, Thrombosis research.

[32]  T. Edgington,et al.  Structural biology of tissue factor, the initiator of thrombogenesis in vivo 1 , 1994, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  A. Varki.  Trousseau's syndrome: multiple definitions and multiple mechanisms. , 2007, Blood.

[34]  M. Sogayar,et al.  Ixolaris, a tissue factor inhibitor, blocks primary tumor growth and angiogenesis in a glioblastoma model , 2009, Journal of thrombosis and haemostasis : JTH.

[35]  S. Shirasawa,et al.  Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. , 2005, Blood.

[36]  Y Sheng,et al.  Proteinase-activated receptor 2 expression in breast cancer and its role in breast cancer cell migration , 2009, Oncogene.

[37]  H. Dvorak,et al.  Tumor shedding and coagulation. , 1981, Science.

[38]  K. Tsuchiya,et al.  Circulating platelet-derived microparticles with procoagulant activity may be a potential cause of thrombosis in uremic patients. , 2002, Kidney international.

[39]  D. Scadden,et al.  Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis , 2012, Proceedings of the National Academy of Sciences.

[40]  J. Fleckner,et al.  Transcriptional program induced by factor VIIa‐tissue factor, PAR1 and PAR2 in MDA‐MB‐231 cells , 2007, Journal of thrombosis and haemostasis : JTH.

[41]  N. Mackman,et al.  Microvesicles as risk markers for venous thrombosis , 2013, Expert review of hematology.

[42]  A. Khorana,et al.  Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy , 2007, Journal of thrombosis and haemostasis : JTH.

[43]  S. Fan,et al.  Tissue factor expression correlates with tumor angiogenesis and invasiveness in human hepatocellular carcinoma. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[44]  T S Edgington,et al.  Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Erwin G. Van Meir,et al.  PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. , 2005, Cancer research.

[46]  A. Mencalha,et al.  Increased expression of protease-activated receptor 1 (PAR-1) in human leukemias. , 2011, Blood cells, molecules & diseases.

[47]  J. Degen,et al.  Factor XIII transglutaminase supports hematogenous tumor cell metastasis through a mechanism dependent on natural killer cell function , 2008, Journal of thrombosis and haemostasis : JTH.

[48]  J. Freyssinet,et al.  Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide. , 1994, Journal of immunology.

[49]  David R. Nadeau,et al.  Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[50]  H. Versteeg,et al.  Cooperation of tissue factor cytoplasmic domain and PAR2 signaling in breast cancer development. , 2010, Blood.

[51]  M. Andrassy,et al.  Tissue Factor – A Receptor Involved in the Control of Cellular Properties, Including Angiogenesis , 2001, Thrombosis and Haemostasis.

[52]  H. Dvorak,et al.  Procoagulant activity associated with plasma membrane vesicles shed by cultured tumor cells. , 1983, Cancer research.

[53]  M. Bromberg,et al.  Role of Protease-activated Receptor 1 in Tumor Metastasis Promoted by Tissue Factor , 2001, Thrombosis and Haemostasis.

[54]  M. Levine,et al.  Epidemiology of Thrombosis in Cancer , 2001, Acta Haematologica.

[55]  R. Hoffman,et al.  Cancer and thrombosis revisited. , 2001, Blood reviews.

[56]  M. Monreal,et al.  Bleeding complications associated with anticoagulant therapy in patients with cancer. , 2010, Thrombosis research.

[57]  A. Agarwal,et al.  PAR1 Is a Matrix Metalloprotease-1 Receptor that Promotes Invasion and Tumorigenesis of Breast Cancer Cells , 2005, Cell.

[58]  J. Ribeiro,et al.  Lufaxin, a Novel Factor Xa Inhibitor From the Salivary Gland of the Sand Fly Lutzomyia longipalpis Blocks Protease-Activated Receptor 2 Activation and Inhibits Inflammation and Thrombosis In Vivo , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[59]  G. Neufeld,et al.  Oncogenic transformation induces tumor angiogenesis: a role for PAR1 activation , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[60]  A. Trousseau.  Phlegmasia alba dolens. , 1865 .

[61]  W. Morain,et al.  Cellular Localization of Enzymatically Active Thrombin in Intact Human Tissues by Hirudin Binding , 1995, Thrombosis and Haemostasis.

[62]  Ruth J. Muschel,et al.  Coagulation Facilitates Tumor Cell Spreading in the Pulmonary Vasculature during Early Metastatic Colony Formation , 2004, Cancer Research.

[63]  M. Ogawa,et al.  Expression of proteinase-activated receptor-2 in human pancreatic cancer: a possible relation to cancer invasion and induction of fibrosis. , 2003, International journal of oncology.

[64]  F. Rumjanek,et al.  Evidence for increased expression of tissue factor and protease-activated receptor-1 in human esophageal cancer. , 2009, Oncology reports.

[65]  A. Varki,et al.  Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. , 2003, The Journal of clinical investigation.

[66]  J. Ribeiro,et al.  Ixolaris: a factor Xa heparin-binding exosite inhibitor. , 2005, The Biochemical journal.

[67]  J. Andersen,et al.  Inhibition of tissue factor by ixolaris reduces primary tumor growth and experimental metastasis in a murine model of melanoma. , 2012, Thrombosis research.

[68]  J. Andersen,et al.  Ixolaris binding to factor X reveals a precursor state of factor Xa heparin‐binding exosite , 2007, Protein science : a publication of the Protein Society.

[69]  Y. Takada,et al.  Hemostasis, Thrombosis, and Vascular Biology: Inhibition of tissue factor signaling suppresses tumor growth , 2014 .

[70]  C. Dunwiddie,et al.  Cellular Localization of Activated Factor X by Xa-Specific Probes , 1991, Thrombosis and Haemostasis.

[71]  R. Bertina,et al.  Microparticle‐associated tissue factor activity: a link between cancer and thrombosis? , 2007, Journal of thrombosis and haemostasis : JTH.

[72]  L. G. Lima,et al.  Simultaneous tissue factor expression and phosphatidylserine exposure account for the highly procoagulant pattern of melanoma cell lines , 2009, Melanoma research.

[73]  P. Reitsma,et al.  The relationship between tissue factor and cancer progression: insights from bench and bedside. , 2012, Blood.

[74]  I. Fidler,et al.  Inhibition of murine melanoma experimental metastasis by recombinant desulfatohirudin, a highly specific thrombin inhibitor. , 1991, Cancer research.

[75]  K. Min,et al.  Mucin‐producing adenocarcinomas and nonbacterial thrombotic endocarditis. Pathogenetic role of tumor mucin , 1980, Cancer.

[76]  W. Ruf,et al.  Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[77]  Ralph H. Hruban,et al.  Tissue Factor Expression, Angiogenesis, and Thrombosis in Pancreatic Cancer , 2007, Clinical Cancer Research.

[78]  Zhiwei Hu,et al.  Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and-independent mechanisms. , 2007, Blood.

[79]  W. Ruf,et al.  Specificity of coagulation factor signaling , 2003, Journal of thrombosis and haemostasis : JTH.

[80]  M. Barcinski,et al.  Tumor-derived microvesicles modulate the establishment of metastatic melanoma in a phosphatidylserine-dependent manner. , 2009, Cancer letters.

[81]  J. Degen,et al.  Mechanisms linking tumor cell-associated procoagulant function to tumor metastasis. , 2007, Thrombosis research.

[82]  J. Rak,et al.  Tissue factor in tumour progression. , 2009, Best practice & research. Clinical haematology.

[83]  R. Monteiro,et al.  Protease-activated receptor-2 (PAR2) mediates VEGF production through the ERK1/2 pathway in human glioblastoma cell lines , 2012 .

[84]  J. Freyssinet,et al.  Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. , 2000, Circulation.

[85]  A. Kakkar,et al.  Cancer-associated thrombosis , 2010, British Journal of Cancer.

[86]  J. Andersen,et al.  Ixolaris, a novel recombinant tissue factor pathway inhibitor (TFPI) from the salivary gland of the tick, Ixodes scapularis: identification of factor X and factor Xa as scaffolds for the inhibition of factor VIIa/tissue factor complex. , 2002, Blood.

[87]  V. Rumjanek,et al.  Assembly and regulation of prothrombinase complex on B16F10 melanoma cells. , 2005, Thrombosis research.

[88]  S. Karpatkin,et al.  Thrombin induces tumor growth, metastasis, and angiogenesis: Evidence for a thrombin-regulated dormant tumor phenotype. , 2006, Cancer cell.

[89]  J. Yeh,et al.  Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer. , 2012, Blood.

[90]  S. Coughlin,et al.  Thrombin signalling and protease-activated receptors , 2000, Nature.

[91]  S. Hirohashi,et al.  Prognostic Significance of Tissue Factor in Pancreatic Ductal Adenocarcinoma , 2005, Clinical Cancer Research.

[92]  C. Miki,et al.  Expression of tissue factor and vascular endothelial growth factor is associated with angiogenesis in colorectal cancer , 2002, American journal of hematology.

[93]  A. Varki,et al.  Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. , 2011, Blood.

[94]  L. Rydén,et al.  Evidence for tissue factor phosphorylation and its correlation with protease‐activated receptor expression and the prognosis of primary breast cancer , 2009, International journal of cancer.

[95]  C. Bokemeyer,et al.  Tissue factor procoagulant activity of plasma microparticles in patients with cancer-associated disseminated intravascular coagulation , 2008, Annals of Hematology.

[96]  H. Büller,et al.  Cancer and thrombosis: from molecular mechanisms to clinical presentations , 2007, Journal of thrombosis and haemostasis : JTH.

[97]  N. Nguyen,et al.  Disseminated Intravascular Coagulation in Solid Tumors: Clinical and Pathologic Study , 2001, Thrombosis and Haemostasis.

[98]  T. Hembrough,et al.  Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism. , 2003, Cancer research.

[99]  B. Østerud,et al.  Tissue factor: (patho)physiology and cellular biology , 2004, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[100]  J. Biggerstaff,et al.  Hemostasis and Malignancy , 1998, Seminars in thrombosis and hemostasis.

[101]  D. Lombardo,et al.  Cancer cell–derived microparticles bearing P-selectin glycoprotein ligand 1 accelerate thrombus formation in vivo , 2009, The Journal of experimental medicine.

[102]  O. Matsubara,et al.  Expression of tissue factor in non-small-cell lung cancers and its relationship to metastasis , 1999, British Journal of Cancer.

[103]  G. Escolar,et al.  Tissue factor in microvesicles shed from U87MG human glioblastoma cells induces coagulation, platelet aggregation, and thrombogenesis. , 1984, Blood.

[104]  P. Carmeliet,et al.  Regulation of angiogenesis by tissue factor cytoplasmic domain signaling , 2004, Nature Medicine.

[105]  A A Rimm,et al.  Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. , 1999, Medicine.

[106]  S. Eichinger,et al.  Tissue factor-positive microparticles: Cellular origin and association with coagulation activation in patients with colorectal cancer , 2006, Thrombosis and Haemostasis.

[107]  S. Coughlin,et al.  Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. , 2004, Blood.

[108]  U. Pendurthi,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. , 2004, Blood.

[109]  W. Ruf,et al.  Protease-activated Receptor 2-dependent Phosphorylation of the Tissue Factor Cytoplasmic Domain* , 2004, Journal of Biological Chemistry.

[110]  K. Mann,et al.  Tumor cell generation of thrombin via functional prothrombinase assembly. , 1985, Cancer research.

[111]  J. Rak,et al.  Tissue factor in cancer and angiogenesis: the molecular link between genetic tumor progression, tumor neovascularization, and cancer coagulopathy. , 2006, Seminars in thrombosis and hemostasis.

[112]  J. Andersen,et al.  Hematophagy and Inhibition of the Extrinsic and Intrinsic Tenase Complexes , 2010 .

[113]  J. Badimón,et al.  Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor. , 2000, Blood.

[114]  Lei Zhao,et al.  Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. , 2012, Blood.

[115]  S. Coughlin,et al.  Protease‐activated receptors in hemostasis, thrombosis and vascular biology , 2005, Journal of thrombosis and haemostasis : JTH.

[116]  S. Karpatkin,et al.  Microthrombocytosis and Platelet Fragmentation Associated with Idiopathic/Autoimmune Thrombocytopenic Purpura , 1975, British journal of haematology.

[117]  J. Degen,et al.  Hemostatic factors, innate immunity and malignancy. , 2012, Thrombosis research.

[118]  S. Barni,et al.  Venous thromboembolism and cancer: new issues for an old topic. , 2003, Critical reviews in oncology/hematology.

[119]  J. Degen,et al.  Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. , 2005, Blood.

[120]  Paolo Prandoni,et al.  Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. , 2002, Blood.

[121]  T. Luther,et al.  Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. , 1994, The Journal of clinical investigation.

[122]  J. Trejo,et al.  Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells. , 2006, Cancer research.

[123]  J. McNiff,et al.  Ancylostoma caninum Anticoagulant Peptide Blocks Metastasis In Vivo and Inhibits Factor Xa Binding to Melanoma Cells In Vitro , 1998, Thrombosis and Haemostasis.

[124]  W. Ruf,et al.  Orchestration of coagulation protease signaling by tissue factor. , 2002, Trends in cardiovascular medicine.

[125]  M. Donati,et al.  Cancer and Thrombosis: from Phlegmasia Alba Dolens to Transgenic Mice , 1995, Thrombosis and Haemostasis.

[126]  Juliette Martin,et al.  Platelet-leukocyte aggregates and derived microparticles in inflammation, vascular remodelling and thrombosis. , 2006, Frontiers in bioscience : a journal and virtual library.

[127]  A. Guha,et al.  Tissue factor regulation by epidermal growth factor receptor and epithelial-to-mesenchymal transitions: effect on tumor initiation and angiogenesis. , 2008, Cancer research.

[128]  M. Sefton,et al.  Platelet-derived microparticle formation involves glycoprotein IIb-IIIa. Inhibition by RGDS and a Glanzmann's thrombasthenia defect. , 1993, The Journal of biological chemistry.

[129]  C. Bucana,et al.  Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes. , 1991, Cancer research.

[130]  Robert Kay,et al.  Expression cloning of oncogenes by retroviral transfer of cDNA libraries , 1995, Molecular and cellular biology.

[131]  W. Ruf,et al.  The tick‐derived inhibitor Ixolaris prevents tissue factor signaling on tumor cells , 2012, Journal of thrombosis and haemostasis : JTH.

[132]  H. Versteeg,et al.  Protease-activated receptor (PAR) 2, but not PAR1, signaling promotes the development of mammary adenocarcinoma in polyoma middle T mice. , 2008, Cancer research.

[133]  J. Rak,et al.  Microvesicles as mediators of intercellular communication in cancer—the emerging science of cellular ‘debris’ , 2011, Seminars in Immunopathology.

[134]  A. Abo,et al.  rNAPc2 Inhibits Colorectal Cancer in Mice through Tissue Factor , 2009, Clinical Cancer Research.