Mechanisms Linking Tumor Cell–Associated Procoagulant Function to Tumor Dissemination

ABSTRACT

There is a persuasive body of evidence suggesting that tissue factor (TF) is a major determinant of tumor progression. In addition to its “traditional” function as the initiator of hemostasis, TF may support tumor progression through signaling mechanisms involving either direct signal transduction through the TF cytoplasmic domain or TF:F VIIa–mediated and TF/F VIIa/F Xa–mediated activation of protease-activated receptors. Whereas TF-mediated signaling events uncoupled from hemostasis may play an important role in tumor dissemination in some contexts, TF-mediated thrombin generation appears to be the major mechanism linking tumor cell–associated TF to metastasis. At least one mechanism coupling thrombin generation to metastatic potential involves the most distal components of the hemostatic system (i.e., platelets, fibrinogen, and factor XIII) and leads to a restriction in natural killer cell–mediated lysis of newly formed micrometastases. A detailed understanding of the mechanisms linking TF and circulating hemostatic system components to tumor progression may lead to novel therapeutic targets for cancer treatment.

KEYWORDS

Hemostatic factors - cancer - NK cells - metastasis

REFERENCES

• 1 Han L Y, Landen Jr C N, Kamat A A et al.. Preoperative serum tissue factor levels are an independent prognostic factor in patients with ovarian carcinoma.  J Clin Oncol. 2006;  24 755-761
• 2 Kaido T, Oe H, Yoshikawa A et al.. Tissue factor is a useful prognostic factor of recurrence in hepatocellular carcinoma in 5-year survivors.  Hepatogastroenterology. 2005;  52 1383-1387
• 3 Nitori N, Ino Y, Nakanishi Y et al.. Prognostic significance of tissue factor in pancreatic ductal adenocarcinoma.  Clin Cancer Res. 2005;  11 2531-2539
• 4 Poon R T, Lau C P, Ho J W et al.. Tissue factor expression correlates with tumor angiogenesis and invasiveness in human hepatocellular carcinoma.  Clin Cancer Res. 2003;  9 5339-5345
• 5 Yamashita H, Kitayama J, Ishikawa M, Nagawa H. Tissue factor expression is a clinical indicator of lymphatic metastasis and poor prognosis in gastric cancer with intestinal phenotype.  J Surg Oncol. 2007;  95 324-353
• 6 Yu J L, May L, Klement P, Weitz J I, Rak J. Oncogenes as regulators of tissue factor expression in cancer: implications for tumor angiogenesis and anti-cancer therapy.  Semin Thromb Hemost. 2004;  30 21-30
• 7 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
• 8 Milsom C, Yu J, May L et al.. The role of tumor-and host-related tissue factor pools in oncogene-driven tumor progression.  Thromb Res. 2007;  120(Suppl 2) S82-S91
• 9 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
• 10 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
• 11 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
• 12 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
• 13 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
• 14 Luther T, Dittert D D, Kotzsch M et al.. Functional implications of tissue factor localization to cell-cell contacts in myocardium.  J Pathol. 2000;  192 121-130
• 15 Ott I, Fischer E G, Miyagi Y, Mueller B M, Ruf W. A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280.  J Cell Biol. 1998;  140 1241-1253
• 16 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
• 17 Sharma L, Melis E, Hickey M J et al.. The cytoplasmic domain of tissue factor contributes to leukocyte recruitment and death in endotoxemia.  Am J Pathol. 2004;  165 331-340
• 18 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
• 19 Jiang X, Guo Y L, Bromberg M E. Formation of tissue factor-factor VIIa-factor Xa complex prevents apoptosis in human breast cancer cells.  Thromb Haemost. 2006;  96 196-201
• 20 Toomey J R, Kratzer K E, Lasky N M, Broze Jr G J. Effect of tissue factor deficiency on mouse and tumor development.  Proc Natl Acad Sci USA. 1997;  94 6922-6926
• 21 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
• 22 Belting M, Dorrell M I, Sandgren S et al.. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling.  Nat Med. 2004;  10 502-509
• 23 Bach R R. Tissue factor encryption.  Arterioscler Thromb Vasc Biol. 2006;  26 456-461
• 24 Bach R R, Moldow C F. Mechanism of tissue factor activation on HL-60 cells.  Blood. 1997;  89 3270-3276
• 25 Wolberg A S, Monroe D M, Roberts H R, Hoffman M R. Tissue factor de-encryption: ionophore treatment induces changes in tissue factor activity by phosphatidylserine-dependent and -independent mechanisms.  Blood Coagul Fibrinolysis. 1999;  10 201-210
• 26 Del Conde I, Shrimpton C N, Thiagarajan P, Lopez J A. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation.  Blood. 2005;  106 1604-1611
• 27 Dietzen D J, Page K L, Tetzloff T A. Lipid rafts are necessary for tonic inhibition of cellular tissue factor procoagulant activity.  Blood. 2004;  103 3038-3044
• 28 Mandal S K, Iakhiaev A, Pendurthi U R, Rao L V. Acute cholesterol depletion impairs functional expression of tissue factor in fibroblasts: modulation of tissue factor activity by membrane cholesterol.  Blood. 2005;  105 153-160
• 29 Bach R, Konigsberg W H, Nemerson Y. Human tissue factor contains thioester-linked palmitate and stearate on the cytoplasmic half-cystine.  Biochemistry. 1988;  27 4227-4231
• 30 Zacharias D A, Violin J D, Newton A C, Tsien R Y. Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells.  Science. 2002;  296 913-916
• 31 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
• 32 Chen V M, Ahamed J, Versteeg H H et al.. Evidence for activation of tissue factor by an allosteric disulfide bond.  Biochemistry. 2006;  45 12020-12028
• 33 Versteeg H H, Schaffner F, Kerver M et al.. Inhibition of tissue factor signaling suppresses tumor growth.  Blood. 2008;  111 190-199
• 34 Pendurthi U R, Ghosh S, Mandal S K, Rao L V. Tissue factor activation: is disulfide bond switching a regulatory mechanism?.  Blood. 2007;  110 3900-3908
• 35 Bobek V, Kovarik J. Antitumor and antimetastatic effect of warfarin and heparins.  Biomed Pharmacother. 2004;  58 213-219
• 36 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
• 37 Palumbo J S, Mullins E, Degen J L. Genetic analysis of hemostatic factors in cancer. In: Khorana AA, Francis CW Cancer-associated Thrombosis: New Findings in Translational Science, Prevention and Treatment. London, UK; Taylor & Francis 2007: 51-63
• 38 Amirkhosravi A, Mousa S A, Amaya M et al.. Inhibition of tumor cell-induced platelet aggregation and lung metastasis by the oral GpIIb/IIIa antagonist XV454.  Thromb Haemost. 2003;  90 549-554
• 39 Honn K V, Cicone B, Skoff A. Prostacyclin: a potent antimetastatic agent.  Science. 1981;  212 1270-1272
• 40 Honn K V, Tang D G, Crissman J D. Platelets and cancer metastasis: a causal relationship?.  Cancer Metastasis Rev. 1992;  11 325-351
• 41 Kato Y, Fujita N, Yano H, Tsuruo T. Suppression of experimental lung colonization of mouse colon adenocarcinoma 26 in vivo by an anti-idiotype monoclonal antibody recognizing a platelet surface molecule.  Cancer Res. 1997;  57 3040-3045
• 42 Pearlstein E, Ambrogio C, Karpatkin S. Effect of antiplatelet antibody on the development of pulmonary metastases following injection of CT26 colon adenocarcinoma, Lewis lung carcinoma, and B16 amelanotic melanoma tumor cells into mice.  Cancer Res. 1984;  44 3884-3887
• 43 Trikha M, Zhou Z, Timar J et al.. Multiple roles for platelet GPIIb/IIIa and alphavbeta3 integrins in tumor growth, angiogenesis, and metastasis.  Cancer Res. 2002;  62 2824-2833
• 44 Tzanakakis G N, Agarwal K C, Veronikis D K, Vezeridis M P. Effects of antiplatelet agents alone or in combinations on platelet aggregation and on liver metastases from a human pancreatic adenocarcinoma in the nude mouse.  J Surg Oncol. 1991;  48 45-50
• 45 Camerer E, Qazi A A, Duong D N et al.. Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis.  Blood. 2004;  104 397-401
• 46 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
• 47 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
• 48 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
• 49 Palumbo J S, Barney K A, Blevins E A et al.. Factor XIII transglutaminase supports hematogenous tumor cell metastasis through a mechanism dependent on natural killer cell function.  J Thromb Haemost. 2008;  6 812-819
• 50 Sierko E, Wojtukiewicz M Z. Platelets and angiogenesis in malignancy.  Semin Thromb Hemost. 2004;  30 95-108
• 51 Dvorak H F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.  N Engl J Med. 1986;  315 1650-1659
• 52 Simpson-Haidaris P J, Rybarczyk B. Tumors and fibrinogen. The role of fibrinogen as an extracellular matrix protein.  Ann N Y Acad Sci. 2001;  936 406-425
• 53 Dardik R, Leor J, Skutelsky E et al.. Evaluation of the pro-angiogenic effect of factor XIII in heterotopic mouse heart allografts and FXIII-deficient mice.  Thromb Haemost. 2006;  95 546-550
• 54 Dardik R, Loscalzo J, Eskaraev R, Inbal A. Molecular mechanisms underlying the proangiogenic effect of factor XIII.  Arterioscler Thromb Vasc Biol. 2005;  25 526-532
• 55 Dardik R, Loscalzo J, Inbal A. Factor XIII (FXIII) and angiogenesis.  J Thromb Haemost. 2006;  4 19-25
• 56 Dardik R, Solomon A, Loscalzo J et al.. Novel proangiogenic effect of factor XIII associated with suppression of thrombospondin 1 expression.  Arterioscler Thromb Vasc Biol. 2003;  23 1472-1477
• 57 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
• 58 Nieswandt B, Hafner M, Echtenacher B, Mannel D N. Lysis of tumor cells by natural killer cells in mice is impeded by platelets.  Cancer Res. 1999;  59 1295-1300
• 59 Degen J L, Bugge T H, Goguen J D. Fibrin and fibrinolysis in infection and host defense.  J Thromb Haemost. 2007;  5(Suppl 1) 24-31
• 60 Flick M J, Du X, Witte D P et al.. Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo.  J Clin Invest. 2004;  113 1596-1606
• 61 Flick M J, LaJeunesse C M, Talmage K E et al.. Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif.  J Clin Invest. 2007;  117 3224-3235
• 62 Marty I, Peclat V, Kirdaite G et al.. Amelioration of collagen-induced arthritis by thrombin inhibition.  J Clin Invest. 2001;  107 631-640
• 63 Rothfork J M, Dessus-Babus S, Van Wamel W J, Cheung A L, Gresham H D. Fibrinogen depletion attenuates Staphyloccocus aureus infection by preventing density-dependent virulence gene up-regulation.  J Immunol. 2003;  171 5389-5395
• 64 Bobryshev Y V, Lord R S. Identification of natural killer cells in human atherosclerotic plaque.  Atherosclerosis. 2005;  180 423-427
• 65 Somersalo K. Migratory functions of natural killer cells.  Nat Immun. 1996;  15 117-133
• 66 Bellone G, Aste-Amezaga M, Trinchieri G, Rodeck U. Regulation of NK cell functions by TGF-beta 1.  J Immunol. 1995;  155 1066-1073
• 67 Yakar I, Melamed R, Shakhar G et al.. Prostaglandin e(2) suppresses NK activity in vivo and promotes postoperative tumor metastasis in rats.  Ann Surg Oncol. 2003;  10 469-479
• 68 Gersuk G M, Chang W C, Pattengale P K. Inhibition of human natural killer cell activity by platelet-derived growth factor. II. Membrane binding studies, effects of recombinant IFN-alpha and IL-2, and lack of effect on T cell and antibody-dependent cellular cytotoxicity.  J Immunol. 1988;  141 4031-4038
• 69 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
• 70 Sun W Y, Witte D P, Degen J L et al.. Prothrombin deficiency results in embryonic and neonatal lethality in mice.  Proc Natl Acad Sci U S A. 1998;  95 7597-7602
• 71 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
• 72 Nierodzik M L, Kajumo F, Karpatkin S. Effect of thrombin treatment of tumor cells on adhesion of tumor cells to platelets in vitro and tumor metastasis in vivo.  Cancer Res. 1992;  52 3267-3272
• 73 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
• 74 Lee A Y. The effects of low molecular weight heparins on venous thromboembolism and survival in patients with cancer.  Thromb Res. 2007;  120(Suppl 2) S121-S127