Thrombin and Cancer: From Molecular Basis to Therapeutic Implications

Massimo Franchini; Pier Mannuccio Mannucci

doi:10.1055/s-0031-1300955

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2012; 38(01): 95-101
DOI: 10.1055/s-0031-1300955

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Thrombin and Cancer: From Molecular Basis to Therapeutic Implications

Massimo Franchini

¹Department of Transfusion Medicine and Hematology, “C. Poma” Hospital, Mantova, Italy

,

Pier Mannuccio Mannucci

²Scientific Direction, IRCCS Cà Granda Foundation Maggiore Hospital, Milan, Italy

› Author Affiliations

Abstract

The relationship between cancer and thrombosis has been recognized for nearly 150 years. Although the mechanisms underlying this association are not completely understood, there are increasing evidences suggesting a pivotal role of thrombin in cancer biology. This review will focus on the most important pathways by which thrombin may affect cancer growth and dissemination. In addition, the potential role of congenital (i.e., hemophilia) and pharmaceutical (i.e., antithrombotic agents) anticoagulation in cancer incidence and survival will be investigated through the analysis of the published experimental and clinical studies.

Keywords

thrombin - cancer - hemophilia - anticoagulant

Full Text

References

References
1 De Bouillaud S. L’obliteration des veines et de son influence sur la formation des hydropisies partielles: consideration sur la hydropisies passive et general. Arch Gen Med 1823; 1: 188-204
2 Trousseau A . Phlegmasia alba dolens. In: Trousseau A, ed. Clinique Medicinale de l’Hotel-Dieu de Paris. Paris, France: JB Bailliere et fils; 1865 :645–712
3 Otten HM, Prins MH. Venous thromboembolism and occult malignancy. Thromb Res 2001; 102 (6) V187-V194
4 Franchini M, Montagnana M, Targher G, Manzato F, Lippi G. Pathogenesis, clinical and laboratory aspects of thrombosis in cancer. J Thromb Thrombolysis 2007; 24 (1) 29-38
5 Nierodzik ML, Plotkin A, Kajumo F, Karpatkin S. Thrombin stimulates tumor-platelet adhesion in vitro and metastasis in vivo. J Clin Invest 1991; 87 (1) 229-236
6 Buller HR, van Doormaal FF, van Sluis GL, Kamphuisen PW. Cancer and thrombosis: from molecular mechanisms to clinical presentations. J Thromb Haemost 2007; 5 (Suppl 1) 246-254
7 Tsopanoglou NE, Maragoudakis ME. Role of thrombin in angiogenesis and tumor progression. Semin Thromb Hemost 2004; 30 (1) 63-69
8 Hu L, Lee M, Campbell W, Perez-Soler R, Karpatkin S. Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood 2004; 104 (9) 2746-2751
9 Zain J, Huang YQ, Feng X, Nierodzik ML, Li JJ, Karpatkin S. Concentration-dependent dual effect of thrombin on impaired growth/apoptosis or mitogenesis in tumor cells. Blood 2000; 95 (10) 3133-3138
10 Franchini M, Montagnana M, Favaloro EJ, Lippi G. The bidirectional relationship of cancer and hemostasis and the potential role of anticoagulant therapy in moderating thrombosis and cancer spread. Semin Thromb Hemost 2009; 35 (7) 644-653
11 Lippi G, Franchini M, Guidi GC. Diagnostic approach to inherited bleeding disorders. Clin Chem Lab Med 2007; 45 (1) 2-12
12 Ruf W, Mueller BM. Thrombin generation and the pathogenesis of cancer. Semin Thromb Hemost 2006; 32 (Suppl 1) 61-68
13 Snyder KM, Kessler CM. The pivotal role of thrombin in cancer biology and tumorigenesis. Semin Thromb Hemost 2008; 34 (8) 734-741
14 Nierodzik ML, Klepfish A, Karpatkin S. Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastasis in vivo. Thromb Haemost 1995; 74 (1) 282-290
15 O’Reilly MS. Antiangiogenic antithrombin. Semin Thromb Hemost 2007; 33 (7) 660-666
16 Huang YQ, Li JJ, Hu L, Lee M, Karpatkin S. Thrombin induces increased expression and secretion of VEGF from human FS4 fibroblasts, DU145 prostate cells and CHRF megakaryocytes. Thromb Haemost 2001; 86 (4) 1094-1098
17 Wang J, Morita I, Onodera M, Murota SI. Induction of KDR expression in bovine arterial endothelial cells by thrombin: involvement of nitric oxide. J Cell Physiol 2002; 190 (2) 238-250
18 Caunt M, Hu L, Tang T, Brooks PC, Ibrahim S, Karpatkin S. Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis. Cancer Res 2006; 66 (8) 4125-4132
19 Huang YQ, Li JJ, Hu L, Lee M, Karpatkin S. Thrombin induces increased expression and secretion of angiopoietin-2 from human umbilical vein endothelial cells. Blood 2002; 99 (5) 1646-1650
20 Duhamel-Clérin E, Orvain C, Lanza F, Cazenave JP, Klein-Soyer C. Thrombin receptor-mediated increase of two matrix metalloproteinases, MMP-1 and MMP-3, in human endothelial cells. Arterioscler Thromb Vasc Biol 1997; 17 (10) 1931-1938
21 Pinedo HM, Verheul HM, D’Amato RJ, Folkman J. Involvement of platelets in tumour angiogenesis?. Lancet 1998; 352 (9142) 1775-1777
22 English D, Garcia JG, Brindley DN. Platelet-released phospholipids link haemostasis and angiogenesis. Cardiovasc Res 2001; 49 (3) 588-599
23 Falanga A, Marchetti M. Heparin in tumor progression and metastatic dissemination. Semin Thromb Hemost 2007; 33 (7) 688-694
24 Mousa SA. Anti-thrombotics in thrombosis and cancer. Future Oncol 2005; 1 (3) 395-403
25 Smorenburg SM, Van Noorden CJ. The complex effects of heparins on cancer progression and metastasis in experimental studies. Pharmacol Rev 2001; 53 (1) 93-105
26 Bobek V, Kovarík J. Antitumor and antimetastatic effect of warfarin and heparins. Biomed Pharmacother 2004; 58 (4) 213-219
27 Weitz IC, Liebman HA. The role of oral anticoagulants in tumor biology. Semin Thromb Hemost 2007; 33 (7) 695-698
28 Langer F, Amirkhosravi A, Ingersoll SB , et al. Experimental metastasis and primary tumor growth in mice with hemophilia A. J Thromb Haemost 2006; 4 (5) 1056-1062
29 Brüggemann LW, Versteeg HH, Niers TM, Reitsma PH, Spek CA. Experimental melanoma metastasis in lungs of mice with congenital coagulation disorders. J Cell Mol Med 2008; 12 (6B) 2622-2627
30 Franchini M, Lippi G, Montagnana M , et al. Hemophilia and cancer: a new challenge for hemophilia centers. Cancer Treat Rev 2009; 35 (4) 374-377
31 Mannucci PM, Schutgens REG, Santagostino E, Mauser-Bunschoten EPM. How I treat age-related morbidities in elderly persons with hemophilia. Blood 2009; 114 (26) 5256-5263
32 Dunn AL. Malignancy in patients with haemophilia: a review of the literature. Haemophilia 2010; 16 (3) 427-436
33 Franchini M, Mannucci PM. Co-morbidities and quality of life in elderly persons with haemophilia. Br J Haematol 2010; 148 (4) 522-533
34 Walker IR, Julian JA. Causes of death in Canadians with haemophilia 1980–1995. Association of Hemophilia Clinic Directors of Canada. Haemophilia 1998; 4 (5) 714-720
35 Darby SC, Kan SW, Spooner RJ , et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007; 110 (3) 815-825
36 Tagliaferri A, Rivolta GF, Iorio A , et al; Italian Association of Hemophilia Centers. Mortality and causes of death in Italian persons with haemophilia, 1990–2007. Haemophilia 2010; 16 (3) 437-446
37 Plug I, Van Der Bom JG, Peters M , et al. Mortality and causes of death in patients with hemophilia, 1992–2001: a prospective cohort study. J Thromb Haemost 2006; 4 (3) 510-516
38 Miesbach W, Alesci S, Krekeler S, Seifried E. Comorbidities and bleeding pattern in elderly haemophilia A patients. Haemophilia 2009; 15 (4) 894-899
39 Sikuler E, Shnaider A, Zilberman D , et al. Hepatitis C virus infection and extrahepatic malignancies. J Clin Gastroenterol 1997; 24 (2) 87-89
40 Miesbach W, Seifried E. Does haemophilia influence cancer-related mortality in HIV-negative patients?. Haemophilia 2011; 17 (1) 55-60
41 Falanga A. The effect of anticoagulant drugs on cancer. J Thromb Haemost 2004; 2 (8) 1263-1265
42 Falanga A, Piccioli A. Effect of anticoagulant drugs in cancer. Curr Opin Pulm Med 2005; 11 (5) 403-407
43 Piccioli A, Falanga A, Prandoni P. Anticoagulants and cancer survival. Semin Thromb Hemost 2006; 32 (8) 810-813
44 Michaels L. Cancer incidence and mortality in patients having anticoagulant therapy. Lancet 1964; 2 (7364) 832-835
45 Zacharski LR, Henderson WG, Rickles FR , et al. Effect of warfarin on survival in small cell carcinoma of the lung. Veterans Administration Study No. 75. JAMA 1981; 245 (8) 831-835
46 Chahinian AP, Propert KJ, Ware JH , et al. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. J Clin Oncol 1989; 7 (8) 993-1002
47 Maurer LH, Herndon II JE, Hollis DR , et al. Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study. J Clin Oncol 1997; 15 (11) 3378-3387
48 Zacharski LR, Henderson WG, Rickles FR , et al. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75. Cancer 1984; 53 (10) 2046-2052
49 Levine M, Hirsh J, Gent M , et al. Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 1994; 343 (8902) 886-889
50 Daly L. The first international urokinase/warfarin trial in colorectal cancer. Clin Exp Metastasis 1991; 9 (1) 3-11
51 Thornes RD, Daly L, Lynch G , et al. Treatment with coumarin to prevent or delay recurrence of malignant melanoma. J Cancer Res Clin Oncol 1994; 120 (Suppl) S32-S34
52 Smorenburg SM, Vink R, Otten HM, Swaneveld F, Büller HR. The effects of vitamin K-antagonists on survival of patients with malignancy: a systematic analysis. Thromb Haemost 2001; 86 (6) 1586-1587
53 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 (26) 1953-1958
54 Tagalakis V, Tamim H, Blostein M, Collet JP, Hanley JA, Kahn SR. Use of warfarin and risk of urogenital cancer: a population-based, nested case-control study. Lancet Oncol 2007; 8 (5) 395-402
55 Akl EA, Kamath G, Kim SY , et al. Oral anticoagulation for prolonging survival in patients with cancer. Cochrane Database Syst Rev 2007; 2 (2) CD006466
56 Tagalakis V, Blostein M, Robinson-Cohen C, Kahn SR. The effect of anticoagulants on cancer risk and survival: systematic review. Cancer Treat Rev 2007; 33 (4) 358-368
57 Robert F. The potential benefits of low-molecular-weight heparins in cancer patients. J Hematol Oncol 2010; 3: 3
58 Kakkar AK, Hedges R, Williamson RCN, Kakkar V. Perioperative heparin-therapy inhibits late death from metastatic cancer. Int J Oncol 1995; 6 (4) 885-888
59 Lebeau B, Chastang C, Brechot JM , et al. Subcutaneous heparin treatment increases survival in small cell lung cancer. “Petites Cellules” Group. Cancer 1994; 74 (1) 38-45
60 Nitti D, Wils J, Sahmoud T , et al; European Organization for Research and Treatment of Cancer. Gastrointestinal Tract Cancer Cooperative Group. Final results of a phase III clinical trial on adjuvant intraportal infusion with heparin and 5-fluorouracil (5-FU) in resectable colon cancer (EORTC GITCCG 1983–1987). Eur J Cancer 1997; 33 (8) 1209-1215
61 Fielding LP, Hittinger R, Grace RH, Fry JS. Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma. Lancet 1992; 340 (8818) 502-506
62 Smorenburg SM, Hettiarachchi RJ, Vink R, Büller HR. The effects of unfractionated heparin on survival in patients with malignancy—a systematic review. Thromb Haemost 1999; 82 (6) 1600-1604
63 Altinbas M, Coskun HS, Er O , et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2004; 2 (8) 1266-1271
64 Kakkar AK, Levine MN, 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 (10) 1944-1948
65 Klerk CP, Smorenburg SM, Otten HM , et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005; 23 (10) 2130-2135
66 Sideras K, Schaefer PL, Okuno SH , et al. Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial. Mayo Clin Proc 2006; 81 (6) 758-767
67 Akl EA, van Doormaal FF, Barba M , et al. Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation. Cochrane Database Syst Rev 2007; 18 (3) CD006652
68 Griffiths GO, Burns S, Noble SI, Macbeth FR, Cohen D, Maughan TS. FRAGMATIC: a randomised phase III clinical trial investigating the effect of fragmin added to standard therapy in patients with lung cancer. BMC Cancer 2009; 9: 355
69 Lee AY, Rickles FR, Julian JA , 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 (10) 2123-2129
70 Lazo-Langner A, Goss GD, Spaans JN, Rodger MA. The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials. J Thromb Haemost 2007; 5 (4) 729-737
71 Kuderer NM, Khorana AA, Lyman GH, Francis CW. A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer 2007; 110 (5) 1149-1161