Semin Thromb Hemost 2019; 45(06): 622-628
DOI: 10.1055/s-0039-1693473
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Decreasing Tumor Growth and Angiogenesis by Inhibition of Coagulation

Yona Nadir
1   Thrombosis and Hemostasis Unit, Department of Hematology, Rambam Health Care Campus, Haifa, Israel
› Author Affiliations
Further Information

Publication History

Publication Date:
09 August 2019 (online)

Abstract

Data regarding the effect of coagulation proteins on enhancing angiogenesis and tumor growth are ample. Thus, inhibition of the coagulation system in an attempt to reduce tumor growth and metastasis seems appealing. However, such molecules as direct oral anticoagulants, warfarin and heparins, may impose a bleeding tendency, limiting the treatment dose that can be used. The heparanase protein, as a cofactor for tissue factor (TF) activity, enhances activation of the coagulation system and in addition has several nonhemostatic effects increasing tumor growth. The molecules currently investigated in the field of cancer and coagulation are heparin mimetics and inhibitors of heparanase derived from TF pathway inhibitor 2. Both groups of molecules are inhibitors of heparanase and in addition pose a low bleeding tendency. Hence, interfering in heparanase activity seems to be a promising target for development of antitumor drugs.

 
  • References

  • 1 Rickles FR, Patierno S, Fernandez PM. Tissue factor, thrombin, and cancer. Chest 2003; 124 (3, Suppl): 58S-68S
  • 2 Versteeg HH, Schaffner F, Kerver M. , et al. Inhibition of tissue factor signaling suppresses tumor growth. Blood 2008; 111 (01) 190-199
  • 3 Bromberg ME, Konigsberg WH, Madison JF, Pawashe A, Garen A. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci U S A 1995; 92 (18) 8205-8209
  • 4 Wang JG, Geddings JE, Aleman MM. , et al. Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer. Blood 2012; 119 (23) 5543-5552
  • 5 Zhao J, Aguilar G, Palencia S, Newton E, Abo A. rNAPc2 inhibits colorectal cancer in mice through tissue factor. Clin Cancer Res 2009; 15 (01) 208-216
  • 6 Tong Y, Yue J, Mao M, Liu Q, Zhou J, Yang J. Recombinant nematode anticoagulant protein c2 inhibits cell invasion by decreasing uPA expression in NSCLC cells. Oncol Rep 2015; 33 (04) 1815-1822
  • 7 Ichikawa J, Cole HA, Magnussen RA. , et al. Thrombin induces osteosarcoma growth, a function inhibited by low molecular weight heparin in vitro and in vivo: procoagulant nature of osteosarcoma. Cancer 2012; 118 (09) 2494-2506
  • 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 (09) 2746-2751
  • 9 Palumbo JS, Kombrinck KW, Drew AF. , et al. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood 2000; 96 (10) 3302-3309
  • 10 Palumbo JS, Talmage KE, Massari JV. , et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 2005; 105 (01) 178-185
  • 11 Eshel R, Ben-Zaken O, Vainas O. , et al. Leukomogenic factors downregulate heparanase expression in acute myeloid leukemia cells. Biochem Biophys Res Commun 2005; 335 (04) 1115-1122
  • 12 De Cicco M. The prothrombotic state in cancer: pathogenic mechanisms. Crit Rev Oncol Hematol 2004; 50 (03) 187-196
  • 13 Carneiro-Lobo TC, Konig S, Machado DE. , et al. Ixolaris, a tissue factor inhibitor, blocks primary tumor growth and angiogenesis in a glioblastoma model. J Thromb Haemost 2009; 7 (11) 1855-1864
  • 14 Morris PE, Steingrub JS, Huang BY. , et al. A phase I study evaluating the pharmacokinetics, safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung injury or acute respiratory distress syndrome. BMC Pulm Med 2012; 12: 5
  • 15 Giugliano RP, Wiviott SD, Stone PH. , et al; ANTHEM-TIMI-32 Investigators. Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial. J Am Coll Cardiol 2007; 49 (25) 2398-2407
  • 16 Vianello F, Sambado L, Goss A, Fabris F, Prandoni P. Dabigatran antagonizes growth, cell-cycle progression, migration, and endothelial tube formation induced by thrombin in breast and glioblastoma cell lines. Cancer Med 2016; 5 (10) 2886-2898
  • 17 Alexander ET, Minton AR, Peters MC, van Ryn J, Gilmour SK. Thrombin inhibition and cisplatin block tumor progression in ovarian cancer by alleviating the immunosuppressive microenvironment. Oncotarget 2016; 7 (51) 85291-85305
  • 18 DeFeo K, Hayes C, Chernick M, Ryn JV, Gilmour SK. Use of dabigatran etexilate to reduce breast cancer progression. Cancer Biol Ther 2010; 10 (10) 1001-1008
  • 19 Shi K, Damhofer H, Daalhuisen J, Ten Brink M, Richel DJ, Spek CA. Dabigatran potentiates gemcitabine-induced growth inhibition of pancreatic cancer in mice. Mol Med 2017; 23: 13-23
  • 20 Guasti L, Squizzato A, Moretto P. , et al. In vitro effects of apixaban on 5 different cancer cell lines. PLoS One 2017; 12 (10) e0185035
  • 21 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 (08) 831-835
  • 22 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
  • 23 Akl EA, Kahale L, Terrenato I. , et al. Oral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev 2014; (06) CD006466
  • 24 Niers TM, Klerk CP, DiNisio M. , et al. Mechanisms of heparin induced anti-cancer activity in experimental cancer models. Crit Rev Oncol Hematol 2007; 61 (03) 195-207
  • 25 Varki NM, Varki A. Heparin inhibition of selectin-mediated interactions during the hematogenous phase of carcinoma metastasis: rationale for clinical studies in humans. Semin Thromb Hemost 2002; 28 (01) 53-66
  • 26 Irimura T, Nakajima M, Nicolson GL. Chemically modified heparins as inhibitors of heparan sulfate specific endo-beta-glucuronidase (heparanase) of metastatic melanoma cells. Biochemistry 1986; 25 (18) 5322-5328
  • 27 Ma Q, Tobu M, Schultz C. , et al. Molecular weight dependent tissue factor pathway inhibitor release by heparin and heparin oligosaccharides. Thromb Res 2007; 119 (05) 653-661
  • 28 Akl EA, Kahale LA, Hakoum MB. , et al. Parenteral anticoagulation in ambulatory patients with cancer. Cochrane Database Syst Rev 2017; 9: CD006652
  • 29 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
  • 30 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
  • 31 Ferro V, Fewings K, Palermo MC, Li C. Large-scale preparation of the oligosaccharide phosphate fraction of Pichia holstii NRRL Y-2448 phosphomannan for use in the manufacture of PI-88. Carbohydr Res 2001; 332 (02) 183-189
  • 32 Liu CJ, Lee PH, Lin DY. , et al. Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage. J Hepatol 2009; 50 (05) 958-968
  • 33 Liu CJ, Chang J, Lee PH. , et al. Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence. World J Gastroenterol 2014; 20 (32) 11384-11393
  • 34 Lewis KD, Robinson WA, Millward MJ. , et al. A phase II study of the heparanase inhibitor PI-88 in patients with advanced melanoma. Invest New Drugs 2008; 26 (01) 89-94
  • 35 Dredge K, Hammond E, Handley P. , et al. PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models. Br J Cancer 2011; 104 (04) 635-642
  • 36 Muhammad RS, Abu-Saleh N, Kinaneh S. , et al. Heparanase inhibition attenuates atherosclerosis progression and liver steatosis in E0 mice. Atherosclerosis 2018; 276: 155-162
  • 37 Ritchie JP, Ramani VC, Ren Y. , et al. SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clin Cancer Res 2011; 17 (06) 1382-1393
  • 38 Pala D, Rivara S, Mor M. , et al. Kinetic analysis and molecular modeling of the inhibition mechanism of roneparstat (SST0001) on human heparanase. Glycobiology 2016; 26 (06) 640-654
  • 39 Zhou H, Roy S, Cochran E. , et al. M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis. PLoS One 2011; 6 (06) e21106
  • 40 Freeman C, Parish CR. Human platelet heparanase: purification, characterization and catalytic activity. Biochem J 1998; 330 (Pt 3): 1341-1350
  • 41 Pikas DS, Li JP, Vlodavsky I, Lindahl U. Substrate specificity of heparanases from human hepatoma and platelets. J Biol Chem 1998; 273 (30) 18770-18777
  • 42 Parish CR, Freeman C, Hulett MD. Heparanase: a key enzyme involved in cell invasion. Biochim Biophys Acta 2001; 1471 (03) M99-M108
  • 43 Vlodavsky I, Friedmann Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J Clin Invest 2001; 108 (03) 341-347
  • 44 Dempsey LA, Brunn GJ, Platt JL. Heparanase, a potential regulator of cell-matrix interactions. Trends Biochem Sci 2000; 25 (08) 349-351
  • 45 Hulett MD, Freeman C, Hamdorf BJ, Baker RT, Harris MJ, Parish CR. Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. Nat Med 1999; 5 (07) 803-809
  • 46 Kussie PH, Hulmes JD, Ludwig DL. , et al. Cloning and functional expression of a human heparanase gene. Biochem Biophys Res Commun 1999; 261 (01) 183-187
  • 47 Toyoshima M, Nakajima M. Human heparanase. Purification, characterization, cloning, and expression. J Biol Chem 1999; 274 (34) 24153-24160
  • 48 Vlodavsky I, Friedmann Y, Elkin M. , et al. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nat Med 1999; 5 (07) 793-802
  • 49 Nadir Y, Brenner B, Zetser A. , et al. Heparanase induces tissue factor expression in vascular endothelial and cancer cells. J Thromb Haemost 2006; 4 (11) 2443-2451
  • 50 Nadir Y, Brenner B, Gingis-Velitski S. , et al. Heparanase induces tissue factor pathway inhibitor expression and extracellular accumulation in endothelial and tumor cells. Thromb Haemost 2008; 99 (01) 133-141
  • 51 Nadir Y, Brenner B, Fux L, Shafat I, Attias J, Vlodavsky I. Heparanase enhances the generation of activated factor X in the presence of tissue factor and activated factor VII. Haematologica 2010; 95 (11) 1927-1934
  • 52 Baker AB, Gibson WJ, Kolachalama VB. , et al. Heparanase regulates thrombosis in vascular injury and stent-induced flow disturbance. J Am Coll Cardiol 2012; 59 (17) 1551-1560
  • 53 Bayam E, Kalçık M, Gürbüz AS. , et al. The relationship between heparanase levels, thrombus burden and thromboembolism in patients receiving unfractionated heparin treatment for prosthetic valve thrombosis. Thromb Res 2018; 171: 103-110
  • 54 Crispel Y, Ghanem S, Attias J, Kogan I, Brenner B, Nadir Y. Involvement of the heparanase procoagulant domain in bleeding and wound healing. J Thromb Haemost 2017; 15 (07) 1463-1472
  • 55 Tatour M, Shapira M, Axelman E. , et al. Thrombin is a selective inducer of heparanase release from platelets and granulocytes via protease-activated receptor-1. Thromb Haemost 2017; 117 (07) 1391-1401
  • 56 Nadir Y, Sarig G, Axelman E. , et al. Heparanase procoagulant activity is elevated and predicts survival in non-small cell lung cancer patients. Thromb Res 2014; 134 (03) 639-642
  • 57 Bitan M, Polliack A, Zecchina G. , et al. Heparanase expression in human leukemias is restricted to acute myeloid leukemias. Exp Hematol 2002; 30 (01) 34-41
  • 58 Kelly T, Miao HQ, Yang Y. , et al. High heparanase activity in multiple myeloma is associated with elevated microvessel density. Cancer Res 2003; 63 (24) 8749-8756
  • 59 Kogan I, Chap D, Hoffman R, Axelman E, Brenner B, Nadir Y. JAK-2 V617F mutation increases heparanase procoagulant activity. Thromb Haemost 2016; 115 (01) 73-80
  • 60 Axelman E, Henig I, Crispel Y. , et al. Novel peptides that inhibit heparanase activation of the coagulation system. Thromb Haemost 2014; 112 (03) 466-477
  • 61 Crispel Y, Axelman E, Tatour M. , et al. Peptides inhibiting heparanase procoagulant activity significantly reduce tumour growth and vascularisation in a mouse model. Thromb Haemost 2016; 116 (04) 669-678
  • 62 Bochenek ML, Bauer T, Gogiraju R. , et al. The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice. Blood Adv 2018; 2 (11) 1300-1314