Heparin in Tumor Progression and Metastatic Dissemination

ABSTRACT

Malignancy is an acquired thrombophilic condition that significantly increases the risk of thrombosis. Both venous and arterial thromboembolisms are recognized complications in patients with cancer. In addition, clotting activation may have a role in tumor progression. The pathogenesis of thrombophilia in cancer is multifactorial; however, an important role is attributed to the tumor cell capacity to interact with and activate the host hemostatic system. Recently, new strategies to prevent and cure thrombosis in cancer have become available, thus improving the management of thrombotic complications in the malignant disease. An antineoplastic effect of anticoagulant agents has also been suggested. Both heparins and vitamin K antagonists have been tested in this context. Heparins have been more extensively studied. Recently, the results of prospective, randomized clinical trials to evaluate the effect of low-molecular-weight heparin on cancer survival have created new interest in this area. The published data are promising and provide new information in the research knowledge in this field. The potential anticancer activity of heparins is supported by data from in vitro and experimental studies.

KEYWORDS

Cancer - heparin - LMWH - UFH - survival - tumor procoagulants - angiogenesis - metastasis

REFERENCES

• 1 Piccioli A, Prandoni P. Venous thromboembolism as first manifestation of cancer.  Acta Haematol. 2001;  106 13-17
• 2 Prandoni P, Lensing A WA, Buller H R et al.. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer.  N Engl J Med. 1992;  327 1128-1133
• 3 Khorana A A, Francis C W, Culakova E, Fisher R I, Kuderer N M, Lyman G H. Thromboembolism in hospitalized neutropenic cancer patients.  J Clin Oncol. 2006;  24 484-490
• 4 Khorana A A, Francis C W, Culakova E, Lyman G H. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study.  Cancer. 2005;  104 2822-2829
• 5 Rickles F R, Levine M N. Epidemiology of thrombosis in cancer.  Acta Haematol. 2001;  106 6-12
• 6 Falanga A, Barbui T, Rickles F R, Levine M N. Guidelines for clotting studies in cancer patients.  Thromb Haemost. 1993;  70 540-542
• 7 Falanga A, Donati M B. Pathogenesis of thrombosis in patients with malignancy.  Int J Hematol. 2001;  73 137-144
• 8 Falanga A, Iacoviello L, Evangelista V et al.. Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia given all-trans-retinoic acid.  Blood. 1995;  86 1072-1084
• 9 Lindhal A K, Sandset P M, Abildgaard U. Indices of hypercoagulation in cancer as compared with those with acute inflammation and acute infarction.  Haemostasis. 1990;  20 253-262
• 10 Seitz R, Rappe N, Kraus M et al.. Activation of coagulation and fibrinolysis in patients with lung cancer: relation to tumour stage and prognosis.  Blood Coag Fibrinolysis. 1993;  4 249-254
• 11 Kakkar A K, DeRuvo N, Chinswangwatanakul V et al.. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor.  Lancet. 1995;  346 1004-1005
• 12 Falanga A, Levine M N, Consonni R et al.. The effect of very low dose warfarin on markers of hypercoagulation in metastatic breast cancer: results from a randomized trial.  Thromb Haemost. 1998;  79 23-27
• 13 Falanga A, Marchetti M, Vignoli A, Balducci D. Clotting mechanisms and cancer: Implications in thrombus formation and tumor progression.  Clin Adv Hematol Oncol. 2003;  1 673-678
• 14 Yu J L, May L, Lhotak V et al.. Oncogenic events regulate tissue factor expression in colorectal cancer: implications for tumor progression and angiogenesis.  Blood. 2005;  105 1734-1741
• 15 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
• 16 Boccaccio C, Sabatino C, Medico E et al.. The METoncogene drives a genetic programme linking cancer to haemostasis.  Nature. 2005;  434 396-400
• 17 Hirsh J, Warkentin T E, Shaughnessy S G et al.. Heparin and low molecular- weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety.  Chest. 2001;  119 64S-94S
• 18 Falanga A. The effect of anticoagulant drugs on cancer.  J Thromb Haemost. 2004;  2 1263-1265
• 19 Zacharski L R, Henderson W G, Rickles F R et al.. Effect of warfarin on survival in small cell carcinoma of the lung.  JAMA. 1981;  245 831-835
• 20 Kakkar A K, Hedges A R, Williamson R CN et al.. Perioperative heparin therapy inhibits late deaths from metastatic cancer.  Int J Oncol. 1995;  6 885-888
• 21 Lebeau B, Chastang C, Brechot J M et al.. Subcutaneous heparin treatment increases survival in small cell lung cancer.  Cancer. 1994;  74 38-44
• 22 Smorenburg S M, Hettiarachchi R J, Vink R et al.. The effects of unfractionated heparin on survival in patients with malignancy-a systematic review.  Thromb Haemost. 1999;  82 1600-1604
• 23 Hettiarachchi R J, Smorenburg S M, Ginsberg J et al.. Do heparins do more than just treat thrombosis? The influence of heparin on cancer spread.  Thromb Haemost. 1999;  82 947-952
• 24 Kakkar A K, Levine M N, 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 1944-1948
• 25 Altinbas M, Coskun H S, 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 1266-1271
• 26 Klerk C P, Smorenburg S M, Otten H M et al.. The effect of low molecular weight heparin on survival in patients with advanced malignancy.  J Clin Oncol. 2005;  23 2130-2135
• 27 Lee A Y, Rickles F R, Julian J A et al.. Randomized comparison of low molecular weight heparin coumarin derivates on the survival of patients with cancer and venous thromboembolism.  J Clin Oncol. 2005;  23 2123-2129
• 28 Sideras K, Schaefer P L, Okuno S H et al.. Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial.  Mayo Clin Proc. 2006;  81 758-767
• 29 Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism.  Lancet Oncol. 2005;  6 401-410
• 30 Falanga A. The effect of anticoagulant drugs on cancer.  J Thromb Haemost. 2004;  2 1263-1265
• 31 Klerk C PW, Smorenburg S M, Buller H R. Antimalignant properties of antithrombotic agents. In: Lugassy G, Falanga A, Kakkar AK, Rickles FR Thrombosis and Cancer. London and New York; Martin Dunitz, Taylor & Francis Group 2004: 207-222
• 32 Tsopanoglou N E, Maragoudakis M E. Role of thrombin in angiogenesis and tumor progression.  Semin Thromb Hemost. 2004;  30 63-69
• 33 Vignoli A, Marchetti M, Balducci D, Barbui T, Falanga A. Differential effect of the low-molecular-weight heparin, dalteparin, and unfractionated heparin on microvascular endothelial cell hemostatic properties.[Erratum in Haematologica 2006;91:620].  Haematologica. 2006;  91 207-214
• 34 Mousa S A, Mohamed S. Inhibition of endothelial cell tube formation by the low molecular weight heparin, tinzaparin, is mediated by tissue factor pathway inibitor.  Thromb Haemost. 2004;  92 627-633
• 35 Rickles F R, Falanga A. Molecular basis for the relationship between thrombosis and cancer.  Thromb Res. 2001;  102 V215-V224
• 36 Borsig L, Wong R, Feramisco J et al.. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis.  Proc Natl Acad Sci USA. 2001;  98 3352-3357
• 37 Niers T M, Klerk C P, DiNisio M et al.. Mechanisms of heparin induced anti-cancer activity in experimental cancer models.  Crit Rev Oncol Hematol. 2007;  61 195-207
• 38 Parish C R, Freeman C, Brown K J et al.. Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity.  Cancer Res. 1999;  59 3433-3441
• 39 Hostettler N, Naggi A, Torri G et al.. P-selectin- and heparanase-dependent antimetastatic activity of non-anticoagulant heparins.  FASEB J. 2007;  6 401-410
• 40 Jayson G C, Gallagher J T. Heparin oligosaccharides: inhibitors of the biological activity of bFGF on Caco-2 cells.  Br J Cancer. 1997;  75 9-16
• 41 Marchetti M, Vignoli A, Russo L et al.. Endothelial capillary tube formation and cell proliferation induced by tumor cells are affected by low molecular weight heparins and unfractionated heparin.  Thromb Res. 2007;  , (in press)
• 42 Balzarotti M, Fontana F, Marras C et al.. In vitro study of low molecular weight heparin effect on cell growth and cell invasion in primary cell cultures of high-grade gliomas.  Oncol Res. 2006;  16 245-250
• 43 Karti S S, Ovali E, Ozgur O et al.. Induction of apoptosis and inhibition of growth of human hepatoma HepG2 cells by heparin.  Hepatogastroenterology. 2003;  50 1864-1866
• 44 Li H L, Ye K H, Zhang H W et al.. Effect of heparin on apoptosis in human nasopharyngeal carcinoma CNE2 cells.  Cell Res. 2001;  11 311-315