Tissue factor procoagulant activity of plasma microparticles is increased in patients with early-stage prostate cancer

Summary

Tissue factor (TF) plays a critical role in tumour growth and metastasis, and its enhanced release into plasma in association with cellular microparticles (MPs) has recently been associated with pathological cancer progression. We have previously demonstrated significantly elevated levels of plasma TF antigen as well as systemic coagulation and platelet activation in patients with localised prostate cancer. In this prospective study, we used a highly sensitive one-stage clotting assay to measure preoperative TF-specific procoagulant activity (PCA) of plasma MPs in 68 consecutive patients with early-stage prostate cancer to further explore the relevance of circulating TF in this tumour entity. Automated calibrated thrombography was used to monitor thrombin generation in cell-free plasma samples in the absence of exogenous TF or phospholipids. Compared to healthy male controls (n=20), patients had significantly increased levels of both D-dimer and TF-specific PCA of plasma MPs (p<0.001). Furthermore, MP-associated TF PCA was higher in patients with (n=29) than in those without (n=39) laboratory evidence of an acute-phase reaction (p=0.004) and decreased to normal levels within one week after radical prostatectomy. Overall, we found a significant correlation between TF-specific PCA of plasma MPs and plasma D-dimer (p=0.002), suggesting that plasma MPs contributed to in-vivo coagulation activation in a TF-dependent manner. Thrombin generation in plasma was also significantly increased in patients compared to controls (p<0.01). Collectively, our findings suggest that TF-specific PCA of plasma MPs contributes to intravascular coagulation activation in patients with early-stage prostate cancer and may represent a potential link between hypercoagulability, inflammation, and disease progression.

Keywords

Microparticles - tissue factor / factor VIIa - cancer

^# The first two authors contributed equally to this work.

• References

• 1 De Cicco M. The prothrombotic state in cancer: pathogenic mechanisms. Crit Rev Oncol Hematol 2004; 50: 187-196.
• 2 Franchini M, Montagnana M, Targher G. et al. Pathogenesis, clinical and laboratory aspects of thrombosis in cancer. J Thromb Thrombolysis 2007; 24: 29-38.
• 3 Kohli M, Fink LM, Spencer HJ. et al. Advanced prostate cancer activates coagulation: a controlled study of activation markers of coagulation in ambulatory patients with localized and advanced prostate cancer. Blood Coagul Fibrinolysis 2002; 13: 1-5.
• 4 Hussain SP, Harris CC. Inflammation and cancer: an ancient link with novel potentials. Int J Cancer 2007; 121: 2373-2380.
• 5 Allavena P, Garlanda C, Borrello MG. et al. Pathways connecting inflammation and cancer. Curr Opin Genet Dev 2008; 18: 3-10.
• 6 Rak J, Milsom C, Yu J. Tissue factor in cancer. Curr Opin Hematol 2008; 15: 522-528.
• 7 Palumbo JS, Talmage KE, Massari JV. 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.
• 8 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.
• 9 Pawlinski R, Pedersen B, Schabbauer G. et al. Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia. Blood 2004; 103: 1342-1347.
• 10 Yu J, May L, Milsom C. et al. Contribution of host-derived tissue factor to tumor neovascularization. Arterioscler Thromb Vasc Biol 2008; 28: 1975-1981.
• 11 Kaushal V, Mukunyadzi P, Siegel ER. et al. Expression of tissue factor in prostate cancer correlates with malignant phenotype. Appl Immunohistochem Mol Morphol 2008; 16: 1-6.
• 12 Akashi T, Furuya Y, Ohta S. et al. Tissue factor expression and prognosis in patients with metastatic prostate cancer. Urology 2003; 62: 1078-1082.
• 13 Ohta S, Wada H, Nakazaki T. et al. Expression of tissue factor is associated with clinical features and angiogenesis in prostate cancer. Anticancer Res 2002; 22: 2991-2996.
• 14 Abdulkadir SA, Carvalhal GF, Kaleem Z. et al. Tissue factor expression and angiogenesis in human prostate carcinoma. Hum Pathol 2000; 31: 443-447.
• 15 Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood 2007; 110: 1723-1729.
• 16 Zwicker JI, Furie BC, Furie B. Cancer-associated thrombosis. Crit Rev Oncol Hematol 2007; 62: 126-136.
• 17 Morel O, Toti F, Hugel B. et al. Procoagulant micro-particles: disrupting the vascular homeostasis equation?. Arterioscler Thromb Vasc Biol 2006; 26: 2594-2604.
• 18 Yu JL, Rak JW. 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.
• 19 Lechner D, Weltermann A. Chemotherapy-induced thrombosis: a role for microparticles and tissue factor?. Semin Thromb Hemost 2008; 34: 199-203.
• 20 Del Conde I, Bharwani LD, Dietzen DJ. et al. Microvesicle-associated tissue factor and Trousseau’s syndrome. J Thromb Haemost 2007; 5: 70-74.
• 21 Tesselaar ME, Romijn FP, Van Der Linden IK. et al. Microparticle-associated tissue factor activity: a link between cancer and thrombosis?. J Thromb Haemost 2007; 5: 520-527.
• 22 Zwicker JI. Tissue factor-bearing microparticles and cancer. Semin Thromb Hemost 2008; 34: 195-198.
• 23 Langer F, Spath B, Haubold K. et al. Tissue factor procoagulant activity of plasma microparticles in patients with cancer-associated disseminated intravascular coagulation. Ann Hematol 2008; 87: 451-457.
• 24 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.
• 25 Tilley RE, Holscher T, Belani R. et al. Tissue factor activity is increased in a combined platelet and micro-particle sample from cancer patients. Thromb Res 2008; 122: 604-609.
• 26 Rak J, Yu JL, Luyendyk J. et al. Oncogenes, trousseau syndrome, and cancer-related changes in the coagulome of mice and humans. Cancer Res 2006; 66: 10643-10646.
• 27 Yu JL, May L, Lhotak V. et al. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angio-genesis. Blood 2005; 105: 1734-1741.
• 28 Langer F, Chun KHF, Amirkhosravi A. et al. Plasma tissue factor antigen in localized prostate cancer: distribution, clinical significance and association with hemostatic activation markers. Thromb Haemost 2007; 97: 464-470.
• 29 Satta N, Toti F, Feugeas O. et al. Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide. J Immunol 1994; 153: 3245-3255.
• 30 Davila M, Amirkhosravi A, Coll E. et al. Tissue factor-bearing microparticles derived from tumor cells: impact on coagulation activation. J Thromb Haemost 2008; 6: 1517-1524.
• 31 Henriksson CE, Klingenberg O, Ovstebø R. et al. Discrepancy between tissue factor activity and tissue factor expression in endotoxin-induced monocytes is associated with apoptosis and necrosis. Thromb Haemost 2005; 94: 1236-1244.
• 32 Culig Z, Steiner H, Bartsch G. et al. Interleukin-6 regulation of prostate cancer cell growth. J Cell Biochem 2005; 95: 497-505.
• 33 Caruso DJ, Carmack AJ, Lokeshwar VB. et al. Osteopontin and interleukin-8 expression is independently associated with prostate cancer recurrence. Clin Cancer Res 2008; 14: 4111-4118.
• 34 Nieuwland R. Cellular origin of microparticles exposing tissue factor in cancer: a mixed double?. J Thromb Haemost 2008; 6: 1514-1516.
• 35 Nakashima J, Tachibana M, Ueno M. et al. Tumor necrosis factor and coagulopathy in patients with prostate cancer. Cancer Res 1995; 55: 4881-4885.
• 36 Cermak J, Key NS, Bach RR. et al. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993; 82: 513-520.
• 37 Pepys MB, Hawkins PN, Kahan MC. et al. Proinflammatory effects of bacterial recombint human C-reactive protein are caused by contamination with bacterial produczs, not by C-reactive protein itself. Circ Res 2005; 97: e97-103.
• 38 Parhami-Seren B, Butenas S, Krudysz-Amblo J. et al. Immunologic quantitation of tissue factor. J Thromb Haemost 2006; 4: 1747-1755.
• 39 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359: 938-949.
• 40 Signaevsky M, Hobbs J, Doll J. et al. Role of alternatively spliced tissue factor in pancreatic growth and angiogenesis. Semin Thromb Hemost 2008; 34: 161-169.
• 41 Khorana AA, Francis CW, Menzies KE. et al. Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J Thromb Haemost 2008; 6: 1983-1985.
• 42 Nieva J. The clinical significance of circulating tissue factor in prostate cancer. Thromb Haemost 2007; 97: 329-330.
• 43 Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol 1999; 17: 1499-1507.