Heparin in Tumor Progression and Metastatic Dissemination

 

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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.

REFERENCES

• 1 Piccioli A, Prandoni P. Venous thromboembolism as first manifestation of cancer.  Acta Haematol. 2001;  106 13-17
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 5 Rickles F R, Levine M N. Epidemiology of thrombosis in cancer.  Acta Haematol. 2001;  106 6-12
  Google Scholar
• 6 Falanga A, Barbui T, Rickles F R, Levine M N. Guidelines for clotting studies in cancer patients.  Thromb Haemost. 1993;  70 540-542
  PubMedGoogle Scholar
• 7 Falanga A, Donati M B. Pathogenesis of thrombosis in patients with malignancy.  Int J Hematol. 2001;  73 137-144
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 16 Boccaccio C, Sabatino C, Medico E et al.. The METoncogene drives a genetic programme linking cancer to haemostasis.  Nature. 2005;  434 396-400
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 18 Falanga A. The effect of anticoagulant drugs on cancer.  J Thromb Haemost. 2004;  2 1263-1265
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  Google Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 29 Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism.  Lancet Oncol. 2005;  6 401-410
  CrossrefPubMedGoogle Scholar
• 30 Falanga A. The effect of anticoagulant drugs on cancer.  J Thromb Haemost. 2004;  2 1263-1265
  CrossrefPubMedGoogle Scholar
• 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
  Google Scholar
• 32 Tsopanoglou N E, Maragoudakis M E. Role of thrombin in angiogenesis and tumor progression.  Semin Thromb Hemost. 2004;  30 63-69
  Article in Thieme ConnectPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  Google Scholar
• 35 Rickles F R, Falanga A. Molecular basis for the relationship between thrombosis and cancer.  Thromb Res. 2001;  102 V215-V224
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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)
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar

Anna FalangaM.D. 

Department of Hematology, Ospedali Riuniti di Bergamo

Largo Barozzi, 1 24128 Bergamo, Italy

Email: annafalanga@yahoo.com