Differential contribution of tissue factor and Factor XII to thrombin generation triggered by breast and pancreatic cancer cells

Rousseau,Aurélie; Larsen,Annette K.; Van Dreden,Patrick; Sabbah,Michele; Elalamy,Ismail; Gerotziafas,Grigoris T.

doi:10.3892/ijo.2017.4172

Differential contribution of tissue factor and Factor XII to thrombin generation triggered by breast and pancreatic cancer cells

Authors:
- Aurélie Rousseau
- Annette K. Larsen
- Patrick Van Dreden
- Michele Sabbah
- Ismail Elalamy
- Grigoris T. Gerotziafas
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Affiliations: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM U938, Institut Universitaire de Cancérologie, Faculty of Medicine Pierre and Marie Curie (UPMC), Sorbonne Universities, Paris, France, Clinical Research, Diagnostica Stago, Gennevilliers, France
Published online on: October 20, 2017 https://doi.org/10.3892/ijo.2017.4172
Pages: 1747-1756

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Abstract

Most cancer cells trigger thrombin generation (TG) to various extent. In the present study, we dissected the mechanisms responsible for the procoagulant activity of pancreatic adenocarcinoma cells (BXPC3), a highly thrombogenic cancer type, and breast cancer cells (MCF7), a less thombogenic tumor type. TG of normal plasma was assessed by the Thrombinoscope (CAT®) in the presence or absence of cancer cells. TG was also assessed in plasma depleted of clotting factors, in plasma spiked with tissue factor (TF) and/or procoagulant phospholipids, in plasma spiked with an anti-TF monoclonal antibody or with corn trypsin inhibitor (CTI). The presence of alternatively spliced TF (asTF), TF activity (TFa) and cancer procoagulant (CP) levels were determined. TFa and asTF were highly expressed by BXPC3 cells, compared to MCF7 cells, while CP levels were higher in MCF7 cells. BXPC3 cells had a stronger effect on TG than MCF7 cells. Accordingly, anti-TF had more inhibitory activity on TG triggered by BXPC3 cells while CTI had more pronounced inhibitory effect on TG triggered by MCF7 cells. TG enhancement by both BXPC3 and MCF7 cells was mediated by FVII and intrinsic tenase while FXII and FXI were also important for MCF7 cells. The induction of TG by BXPC3 cells was mainly driven by the TF pathway while TG generation triggered by MCF7 cells was also driven by FXII activation. Therefore, hypercoagulability results from a combination of the inherent procoagulant properties of cancer cell-associated TF as well as of procoagulant phospholipids in the plasma microenvironment.

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1	Trousseau A: Clinique Médicale de l'Hôtel-Dieu de Paris. 3. 2nd edition. JB Baillière; Paris: pp. 654–712. 1865
2	Falanga A, Russo L and Milesi V: The coagulopathy of cancer. Curr Opin Hematol. 21:423–429. 2014. View Article : Google Scholar : PubMed/NCBI
3	Khorana AA, Francis CW, Culakova E, Kuderer NM and Lyman GH: Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 5:632–634. 2007. View Article : Google Scholar : PubMed/NCBI
4	Chew HK, Wun T, Harvey D, Zhou H and White RH: Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 166:458–464. 2006. View Article : Google Scholar : PubMed/NCBI
5	Prandoni P, Falanga A and Piccioli A: Cancer and venous thromboembolism. Lancet Oncol. 6:401–410. 2005. View Article : Google Scholar : PubMed/NCBI
6	Lee AY and Levine MN: Venous thromboembolism and cancer: Risks and outcomes. Circulation. 107(Suppl 1): I17–I21. 2003. View Article : Google Scholar : PubMed/NCBI
7	Caine GJ, Stonelake PS, Lip GY and Kehoe ST: The hypercoagulable state of malignancy: Pathogenesis and current debate. Neoplasia. 4:465–473. 2002. View Article : Google Scholar : PubMed/NCBI
8	De Cicco M: The prothrombotic state in cancer: Pathogenic mechanisms. Crit Rev Oncol Hematol. 50:187–196. 2004. View Article : Google Scholar : PubMed/NCBI
9	Roberts HR, Hoffman M and Monroe DM: A cell-based model of thrombin generation. Semin Thromb Hemost. 32(Suppl 1): 32–38. 2006. View Article : Google Scholar : PubMed/NCBI
10	Amin C, Mackman N and Key NS: Microparticles and cancer. Pathophysiol Haemost thromb. 36:177–183. 2008. View Article : Google Scholar
11	Davila M, Amirkhosravi A, Coll E, Desai H, Robles L, Colon J, Baker CH and Francis JL: Tissue factor-bearing microparticles derived from tumor cells: Impact on coagulation activation. J Thromb Haemost. 6:1517–1524. 2008. View Article : Google Scholar : PubMed/NCBI
12	Rauch U and Nemerson Y: Circulating tissue factor and thrombosis. Curr Opin Hematol. 7:273–277. 2000. View Article : Google Scholar : PubMed/NCBI
13	Butenas S, Orfeo T and Mann KG: Tissue factor activity and function in blood coagulation. Thromb Res. 122(Suppl 1): S42–S46. 2008. View Article : Google Scholar : PubMed/NCBI
14	Mackman N: The role of tissue factor and factor VIIa in hemostasis. Anesth Analg. 108:1447–1452. 2009. View Article : Google Scholar : PubMed/NCBI
15	Mutch NJ: Emerging roles for factor XII in vivo. J Thromb Haemost. 9:1355–1358. 2011. View Article : Google Scholar : PubMed/NCBI
16	Müller F and Renné T: Novel roles for factor XII-driven plasma contact activation system. Curr Opin Hematol. 15:516–521. 2008. View Article : Google Scholar : PubMed/NCBI
17	Thomassen MC, Heinzmann AC, Herfs L, Hartmann R, Dockal M, Scheiflinger F, Hackeng TM and Rosing J: Tissue factor-independent inhibition of thrombin generation by tissue factor pathway inhibitor-α. J Thromb Haemost. 13:92–100. 2015. View Article : Google Scholar
18	Nickel KF, Ronquist G, Langer F, Labberton L, Fuchs TA, Bokemeyer C, Sauter G, Graefen M, Mackman N, Stavrou EX, et al: The polyphosphate-factor XII pathway drives coagulation in prostate cancer-associated thrombosis. Blood. 126:1379–1389. 2015. View Article : Google Scholar : PubMed/NCBI
19	Gordon SG and Mielicki WP: Cancer procoagulant: A factor X activator, tumor marker and growth factor from malignant tissue. Blood Coagul Fibrinolysis. 8:73–86. 1997. View Article : Google Scholar : PubMed/NCBI
20	Donati MB, Gambacorti-Passerini C, Casali B, Falanga A, Vannotti P, Fossati G, Semeraro N and Gordon SG: Cancer procoagulant in human tumor cells: Evidence from melanoma patients. Cancer Res. 46:6471–6474. 1986.PubMed/NCBI
21	Gerotziafas GT, Galea V, Mbemba E, Khaterchi A, Sassi M, Baccouche H, Prengel C, van Dreden P, Hatmi M, Bernaudin JF, 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. Thromb Res. 129:779–786. 2012. View Article : Google Scholar
22	Marchetti M, Diani E, Ten Cate H and Falanga A: Characterization of the thrombin generation potential of leukemic and solid tumor cells by calibrated automated thrombography. Haematologica. 97:1173–1180. 2012. View Article : Google Scholar : PubMed/NCBI
23	Van Dreden P, Rousseau A, Savoure A, Lenormand B, Fontaine S and Vasse M: Plasma thrombomodulin activity, tissue factor activity and high levels of circulating procoagulant phospholipid as prognostic factors for acute myocardial infarction. Blood Coagul Fibrinolysis. 20:635–641. 2009. View Article : Google Scholar : PubMed/NCBI
24	Rousseau A, Favier R and Van Dreden P: Elevated circulating soluble thrombomodulin activity, tissue factor activity and circulating procoagulant phospholipids: New and useful markers for pre-eclampsia? Eur J Obstet Gynecol Reprod Biol. 146:46–49. 2009. View Article : Google Scholar : PubMed/NCBI
25	Schneider P, Van Dreden P, Rousseau A, Kassim Y, Legrand E, Vannier JP and Vasse M: Increased levels of tissue factor activity and procoagulant phospholipids during treatment of children with acute lymphoblastic leukaemia. Br J Haematol. 148:582–592. 2010. View Article : Google Scholar
26	Hemker HC, Giesen P, AlDieri R, Regnault V, de Smed E, Wagenvoord R, Lecompte T and Béguin S: The calibrated automated thrombogram (CAT): A universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb. 32:249–253. 2002. View Article : Google Scholar
27	Gerotziafas GT, Depasse F, Busson J, Leflem L, Elalamy I and Samama MM: Towards a standardization of thrombin generation assessment: the influence of tissue factor, platelets and phospholipids concentration on the normal values of Thrombogram-Thrombinoscope assay. Thromb J. 3:162005. View Article : Google Scholar : PubMed/NCBI
28	Tilley RE, Holscher T, Belani R, Nieva J and Mackman N: Tissue factor activity is increased in a combined platelet and microparticle sample from cancer patients. Thromb Res. 122:604–609. 2008. View Article : Google Scholar : PubMed/NCBI
29	Key NS, Chantrathammachart P, Moody PW and Chang JY: Membrane microparticles in VTE and cancer. Thromb Res. 125(Suppl 2): S80–S83. 2010. View Article : Google Scholar : PubMed/NCBI
30	Zwicker JI, Liebman HA, Neuberg D, Lacroix R, Bauer KA, Furie BC and Furie B: Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res. 15:6830–6840. 2009. View Article : Google Scholar : PubMed/NCBI
31	Bogdanov VY, Kirk RI, Miller C, Hathcock JJ, Vele S, Gazdoiu M, Nemerson Y and Taubman MB: Identification and characterization of murine alternatively spliced tissue factor. J Thromb Haemost. 4:158–167. 2006. View Article : Google Scholar : PubMed/NCBI
32	Böing AN, Hau CM, Sturk A and Nieuwland R: Human alternatively spliced tissue factor is not secreted and does not trigger coagulation. J Thromb Haemost. 7:1423–1426. 2009. View Article : Google Scholar : PubMed/NCBI
33	Szotowski B, Antoniak S and Rauch U: Alternatively spliced tissue factor: A previously unknown piece in the puzzle of hemostasis. Trends Cardiovasc Med. 16:177–182. 2006. View Article : Google Scholar : PubMed/NCBI
34	Censarek P, Bobbe A, Grandoch M, Schrör K and Weber AA: Alternatively spliced human tissue factor (asHTF) is not pro-coagulant. Thromb Haemost. 97:11–14. 2007.PubMed/NCBI
35	Spronk HM, Dielis AW, Panova-Noeva M, van Oerle R, Govers-Riemslag JW, Hamulyák K, Falanga A and Cate HT: Monitoring thrombin generation: Is addition of corn trypsin inhibitor needed? Thromb Haemost. 101:1156–1162. 2009.PubMed/NCBI
36	van Veen JJ, Gatt A, Cooper PC, Kitchen S, Bowyer AE and Makris M: Corn trypsin inhibitor in fluorogenic thrombin-generation measurements is only necessary at low tissue factor concentrations and influences the relationship between factor VIII coagulant activity and thrombogram parameters. Blood Coagul Fibrinolysis. 19:183–189. 2008. View Article : Google Scholar : PubMed/NCBI
37	Parhami-Seren B, Butenas S, Krudysz-Amblo J and Mann KG: Immunologic quantification of tissue factors. J Thromb Haemost. 4:1747–1755. 2006. View Article : Google Scholar : PubMed/NCBI
38	Berntorp E and Salvagno GL: Standardization and clinical utility of thrombin-generation assays. Semin Thromb Hemost. 34:670–682. 2008. View Article : Google Scholar : PubMed/NCBI