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Coagulation in Cancer pp 43–66Cite as

The Role of Plasminogen-Plasmin System in Cancer

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Part of the book series: Cancer Treatment and Research ((CTAR,volume 148))

Abstract

Components of the plasminogen-plasmin system participate in a wide variety of physiologic and pathologic processes, including tumor growth, invasion and metastasis, through their effect on angiogenesis and cell migration. These components are found in most tumors and their expression not only signifies their function but also carries a prognostic value. Their expression is in turn modulated by cytokines and growth factors, many of which are up-regulated in cancer. Though both tPA and uPA are expressed in tumor cells, uPA with its receptor (uPAR) is mostly involved in cellular functions, while tPA with its receptor Annexin II on endothelial surface, regulates intravascular fibrin deposition. Among the inhibitors of fibrinolysis, PAI-1 is a major player in the pathogenesis of many vascular diseases as well as in cancer. Therapeutic interventions, either using plasminogen activators or experimental inhibitor agents against PAI-1, have shown encouraging results in experimental tumors but not been verified clinically.

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References

  1. Billroth T. Lectures on surgical pathology and therapeutics. In: A handbook for students and practitioners. London: The New Sydenham Society; 1877–1878;1878.

    Google Scholar 

  2. Iwasaki T. Histological and experimental observations on the destruction of tumor cells in the blood vessels. J Pathol Bacteriol 1912;20:85–104.

    Google Scholar 

  3. O'Meara RA, Jackson RD. Cytological observations on carcinoma. Irish J Med Sci 1958;171(391):327–8.

    Google Scholar 

  4. 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):831–5.

    PubMed  CAS  Google Scholar 

  5. DeWys WD, Kwaan HC, Bathina S. Effect of defibrination on tumor growth and response to chemotherapy. Cancer Res 1976;36(10):3584–7.

    PubMed  CAS  Google Scholar 

  6. Meehan KR, Zacharski LR, Maurer LH, et al. Studies of possible mechanisms for the effect of urokinase therapy in small cell carcinoma of the lung. Blood Coagul Fibrinolysis 1995;6(2):105–12.

    PubMed  CAS  Google Scholar 

  7. Agostino D, Agostino N. Trauma, fibrinogen levels and metastasis formation in experimental oncology. Sangre 1982;27(3):301–7.

    PubMed  CAS  Google Scholar 

  8. Kwaan HC. The plasminogen-plasmin system in malignancy. Cancer Metastasis Rev 1992;11(3–4):291–311.

    PubMed  CAS  Google Scholar 

  9. Petersen TE, Martzen MR, Ichinose A, Davie EW. Characterization of the gene for human plasminogen, a key proenzyme in the fibrinolytic system. J Biol Chem 1990;265(11):6104–11.

    PubMed  CAS  Google Scholar 

  10. Summaria L, Spitz F, Arzadon L, Boreisha IG, Robbins KC. Isolation and characterization of the affinity chromatography forms of human Glu- and Lys-plasminogens and plasmins. J Biol Chem 1976;251(12):3693–9.

    PubMed  CAS  Google Scholar 

  11. Robbins KC, Bernabe P, Arzadon L, Summaria L. NH2-terminal sequences of mammalian plasminogens and plasmin S-carboxymethyl heavy (A) and light (B) chain derivatives. A re-evaluation of the mechanism of activation of plasminogen. J Biol Chem 1973;248(20):7242–6.

    PubMed  CAS  Google Scholar 

  12. Summaria L, Arzadon L, Bernabe P, Robbins KC. Isolation, characterization, and comparison of the S-carboxymethyl heavy (A) and light (B) chain derivatives of cat, dog, rabbit, and bovine plasmins. J Biol Chem 1973;248(18):6522–7.

    PubMed  CAS  Google Scholar 

  13. Robbins KC, Summaria L. Isoelectric focusing of human plasminogen, plasmin, and derived heavy (A) and light (B) chains. Ann N Y Acad Sci 1973;209:397–404.

    PubMed  CAS  Google Scholar 

  14. Robbins KC, Bernabe P, Arzadon L, Summaria L. The primary structure of human plasminogen. II. The histidine loop of human plasmin: light (B) chain active center histidine sequence. J Biol Chem 1973;248(5):1631–3.

    PubMed  CAS  Google Scholar 

  15. Robbins KC, Bernabe P, Arzadon L, Summaria L. The primary structure of human plasminogen. I. The NH 2 -terminal sequences of human plasminogen and the S-carboxymethyl heavy (A) and light (B) chain derivatives of plasmin. J Biol Chem 1972;247(21):6757–62.

    PubMed  CAS  Google Scholar 

  16. Myohanen H, Vaheri A. Regulation and interactions in the activation of cell-associated plasminogen. Cell Mol Life Sci 2004;61(22):2840–58.

    PubMed  CAS  Google Scholar 

  17. Kwaan HC. The biologic role of components of the plasminogen-plasmin system. Progress Cardiovasc Dis 1992;34(5):309–16.

    CAS  Google Scholar 

  18. Vassalli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest 1991;88(4):1067–72.

    PubMed  CAS  Google Scholar 

  19. Bachmann F, Kruithof IE. Tissue plasminogen activator: chemical and physiological aspects. Semin Thromb Hemost 1984;10(1):6–17.

    PubMed  CAS  Google Scholar 

  20. Blasi F, Riccio A, Sebastio G. Human plasminogen activators. Genes and proteins structure. Horiz Biochem Biophys 1986;8:377–414.

    PubMed  CAS  Google Scholar 

  21. Collen D, Lijnen HR. Tissue-type plasminogen activator: a historical perspective and personal account. J Thromb Haemost 2004;2(4):541–6.

    PubMed  CAS  Google Scholar 

  22. Carmeliet P, Schoonjans L, Kieckens L, et al. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 1994;368(6470):419–24.

    PubMed  CAS  Google Scholar 

  23. Kwaan HC, Lo R, McFadzean AJ. On the production of plasma fibrinolytic activity within veins. Clin Sci (Lond) 1957;16(2):241–53.

    CAS  Google Scholar 

  24. Kwaan HC, McFadzean AJ. On plasma fibrinolytic activity induced by ischaemia. Clin Sci (Lond) 1956;15(2):245–57.

    CAS  Google Scholar 

  25. Kwaan HC, Lo R, McFadzean AJ. The production of plasma fibrinolytic activity in vivo by serotonin (5-hydroxytryptamine) creatinine sulphate. Clin Sci (Lond) 1957;16(2):255–9.

    CAS  Google Scholar 

  26. O'Rourke J, Jiang X, Hao Z, Cone RE, Hand AR. Distribution of sympathetic tissue plasminogen activator (tPA) to a distant microvasculature. J Neurosci Res 2005;79(6):727–33.

    PubMed  Google Scholar 

  27. Hajjar KA, Menell JS. Annexin II: a novel mediator of cell surface plasmin generation. Ann N Y Acad Sci 1997;811:337–49.

    PubMed  CAS  Google Scholar 

  28. Hajjar KA, Krishnan S. Annexin II: a mediator of the plasmin/plasminogen activator system. Trends Cardiovasc Med 1999;9(5):128–38.

    PubMed  CAS  Google Scholar 

  29. Menell JS, Cesarman GM, Jacovina AT, McLaughlin MA, Lev EA, Hajjar KA. Annexin II and bleeding in acute promyelocytic leukemia. N Engl J Med 1999;340(13):994–1004.

    PubMed  CAS  Google Scholar 

  30. Bernik MB, Kwaan HC. Origin of fibrinolytic activity in cultures of the human kidney. J Lab Clin Med 1967;70(4):650–61.

    PubMed  CAS  Google Scholar 

  31. Bernik MB, Kwaan HC. Plasminogen activator activity in cultures from human tissues. An immunological and histochemical study. J Clin Invest 1969;48(9):1740–53.

    PubMed  CAS  Google Scholar 

  32. Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev 2002;3(12):932–43.

    CAS  Google Scholar 

  33. Caiolfa VR, Zamai M, Malengo G, et al. Monomer dimer dynamics and distribution of GPI-anchored uPAR are determined by cell surface protein assemblies. J Cell biol 2007;179(5):1067–82.

    PubMed  CAS  Google Scholar 

  34. Nykjaer A, Conese M, Christensen EI, et al. Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. EMBO J 1997;16(10):2610–20.

    PubMed  CAS  Google Scholar 

  35. Gliemann J. Receptors of the low density lipoprotein (LDL) receptor family in man. Multiple functions of the large family members via interaction with complex ligands. Biol Chem 1998;379(8–9):951–64.

    PubMed  CAS  Google Scholar 

  36. Aoki N, Harpel PC. Inhibitors of the fibrinolytic enzyme system. Semin Thromb Hemost 1984;10(1):24–41.

    PubMed  CAS  Google Scholar 

  37. Vaughan DE, De Taeye BM, Eren M. PAI-1 antagonists: predictable indications and unconventional applications. Curr Drug Targets 2007;8(9):962–70.

    PubMed  CAS  Google Scholar 

  38. Stefansson S, McMahon GA, Petitclerc E, Lawrence DA. Plasminogen activator inhibitor-1 in tumor growth, angiogenesis and vascular remodeling. Curr Pharm Des 2003;9(19):1545–64.

    PubMed  CAS  Google Scholar 

  39. Kwaan HC, Wang J, Svoboda K, Declerck PJ. Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. Br J Cancer 2000;82(10):1702–8.

    PubMed  CAS  Google Scholar 

  40. Chen Y, Kelm RJ Jr, Budd RC, Sobel BE, Schneider DJ. Inhibition of apoptosis and caspase-3 in vascular smooth muscle cells by plasminogen activator inhibitor type-1. J Cell Biochem 2004;92(1):178–88.

    PubMed  CAS  Google Scholar 

  41. Nagamine Y, Medcalf RL, Munoz-Canoves P. Transcriptional and posttranscriptional regulation of the plasminogen activator system. Thromb Haemost 2005;93(4):661–75.

    PubMed  CAS  Google Scholar 

  42. Durand MK, Bodker JS, Christensen A, et al. Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis. Thromb Haemost 2004;91(3):438–49.

    PubMed  CAS  Google Scholar 

  43. Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis. J Clin Invest 1995;95(3):995–1001.

    PubMed  CAS  Google Scholar 

  44. Medcalf RL, Stasinopoulos SJ. The undecided serpin. The ins and outs of plasminogen activator inhibitor type 2. FEBS J 2005;272(19):4858–67.

    PubMed  CAS  Google Scholar 

  45. Swartz JM, Bystrom J, Dyer KD, Nitto T, Wynn TA, Rosenberg HF. Plasminogen activator inhibitor-2 (PAI-2) in eosinophilic leukocytes. J Leukocyte Biol 2004;76(4):812–9.

    PubMed  CAS  Google Scholar 

  46. Kruithof EK, Baker MS, Bunn CL. Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood 1995;86(11):4007–24.

    PubMed  CAS  Google Scholar 

  47. Dickinson JL, Norris BJ, Jensen PH, Antalis TM. The C-D interhelical domain of the serpin plasminogen activator inhibitor-type 2 is required for protection from TNF-alpha induced apoptosis. Cell Death Differ 1998;5(2):163–71.

    PubMed  CAS  Google Scholar 

  48. Weiss LM, Warnke RA, Sklar J, Cleary ML. Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. N Engl J Med 1987;317(19):1185–9.

    PubMed  CAS  Google Scholar 

  49. Santin AD, Zhan F, Bellone S, et al. Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy. Int J Cancer 2004;112(1):14–25.

    PubMed  CAS  Google Scholar 

  50. Hasina R, Hulett K, Bicciato S, Di Bello C, Petruzzelli GJ, Lingen MW. Plasminogen activator inhibitor-2: a molecular biomarker for head and neck cancer progression. Cancer Res 2003;63(3):555–9.

    PubMed  CAS  Google Scholar 

  51. Varro A, Noble PJ, Pritchard DM, et al. Helicobacter pylori induces plasminogen activator inhibitor 2 in gastric epithelial cells through nuclear factor-kappaB and RhoA: implications for invasion and apoptosis. Cancer Res 2004;64(5):1695–702.

    PubMed  CAS  Google Scholar 

  52. Bajzar L, Morser J, Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem 1996;271(28):16603–8.

    PubMed  CAS  Google Scholar 

  53. Leurs J, Wissing BM, Nerme V, Schatteman K, Bjorquist P, Hendriks D. Different mechanisms contribute to the biphasic pattern of carboxypeptidase U (TAFIa) generation during in vitro clot lysis in human plasma. Thromb Haemost 2003;89(2):264–71.

    PubMed  CAS  Google Scholar 

  54. Wang W, Boffa MB, Bajzar L, Walker JB, Nesheim ME. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998;273(42):27176–81.

    PubMed  CAS  Google Scholar 

  55. Schneider M, Nesheim M. A study of the protection of plasmin from antiplasmin inhibition within an intact fibrin clot during the course of clot lysis. J Biol Chem 2004;279(14):13333–9.

    PubMed  CAS  Google Scholar 

  56. van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000;95(9):2855–9.

    PubMed  Google Scholar 

  57. Eichinger S, Schonauer V, Weltermann A, et al. Thrombin-activatable fibrinolysis inhibitor and the risk for recurrent venous thromboembolism. Blood 2004;103(10):3773–6.

    PubMed  CAS  Google Scholar 

  58. Meijers JC, Oudijk EJ, Mosnier LO, et al. Reduced activity of TAFI (thrombin-activatable fibrinolysis inhibitor) in acute promyelocytic leukaemia. Br J Haematol 2000;108(3):518–23.

    PubMed  CAS  Google Scholar 

  59. Morange PE, Juhan-Vague I, Scarabin PY, et al. Association between TAFI antigen and Ala147Thr polymorphism of the TAFI gene and the angina pectoris incidence. The PRIME Study (Prospective Epidemiological Study of MI). Thromb Haemost 2003;89(3):554–60.

    PubMed  CAS  Google Scholar 

  60. Montaner J, Ribo M, Monasterio J, Molina CA, Alvarez-Sabin J. Thrombin-activable fibrinolysis inhibitor levels in the acute phase of ischemic stroke. Stroke 2003;34(4):1038–40.

    PubMed  CAS  Google Scholar 

  61. Santamaria A, Oliver A, Borrell M, et al. Risk of ischemic stroke associated with functional thrombin-activatable fibrinolysis inhibitor plasma levels. Stroke 2003;34(10):2387–91.

    PubMed  CAS  Google Scholar 

  62. Reijerkerk A, Meijers JC, Havik SR, Bouma BN, Voest EE, Gebbink MF. Tumor growth and metastasis are not affected in thrombin-activatable fibrinolysis inhibitor-deficient mice. J Thromb Haemost 2004;2(5):769–79.

    PubMed  CAS  Google Scholar 

  63. Dano K, Andreasen PA, Grondahl-Hansen J, Kristensen P, Nielsen LS, Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 1985;44:139–266.

    PubMed  CAS  Google Scholar 

  64. Mignatti P, Rifkin DB. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 1993;73(1):161–95.

    PubMed  CAS  Google Scholar 

  65. Kirchheimer JC, Wojta J, Hienert G, et al. Effect of urokinase on the proliferation of primary cultures of human prostatic cells. Thromb Res 1987;48(3):291–8.

    PubMed  CAS  Google Scholar 

  66. Kirchheimer JC, Wojta J, Christ G, Binder BR. Proliferation of a human epidermal tumor cell line stimulated by urokinase. Faseb J 1987;1(2):125–8.

    PubMed  CAS  Google Scholar 

  67. Soff GA, Sanderowitz J, Gately S, et al. Expression of plasminogen activator inhibitor type 1 by human prostate carcinoma cells inhibits primary tumor growth, tumor-associated angiogenesis, and metastasis to lung and liver in an athymic mouse model. J Clin Invest 1995;96(6):2593–600.

    PubMed  CAS  Google Scholar 

  68. Levenson AS, Kwaan HC, Svoboda KM, Weiss IM, Sakurai S, Jordan VC. Oestradiol regulation of the components of the plasminogen-plasmin system in MDA-MB-231 human breast cancer cells stably expressing the oestrogen receptor. Br J Cancer 1998;78(1):88–95.

    PubMed  CAS  Google Scholar 

  69. McColl BK, Baldwin ME, Roufail S, et al. Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D. J Exp Med 2003;198(6):863–8.

    PubMed  CAS  Google Scholar 

  70. Fredriksson L, Li H, Fieber C, Li X, Eriksson U. Tissue plasminogen activator is a potent activator of PDGF-CC. EMBO J 2004;23(19):3793–802.

    PubMed  CAS  Google Scholar 

  71. Burridge K, Fath K, Kelly T, Nuckolls G, Turner C. Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. Ann Rev Cell Biol 1988;4:487–525.

    PubMed  CAS  Google Scholar 

  72. Takahashi K, Ikeo K, Gojobori T, Tanifuji M. Local function of urokinase receptor at the adhesion contact sites of a metastatic tumor cell. Thromb Res 1990;10:55–61.

    CAS  Google Scholar 

  73. Madsen CD, Ferraris GM, Andolfo A, Cunningham O, Sidenius N. uPAR-induced cell adhesion and migration: vitronectin provides the key. J Cell Biol 2007;177(5):927–39.

    PubMed  CAS  Google Scholar 

  74. Cunningham O, Andolfo A, Santovito ML, Iuzzolino L, Blasi F, Sidenius N. Dimerization controls the lipid raft partitioning of uPAR/CD87 and regulates its biological functions. EMBO J 2003;22(22):5994–6003.

    PubMed  CAS  Google Scholar 

  75. O'Reilly MS, Holmgren L, Shing Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994;79(2):315–28.

    PubMed  Google Scholar 

  76. Gately S, Twardowski P, Stack MS, et al. The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci USA 1997;94(20):10868–72.

    PubMed  CAS  Google Scholar 

  77. Geiger JH, Cnudde SE. What the structure of angiostatin may tell us about its mechanism of action. J Thromb Haemost 2004;2(1):23–34.

    PubMed  CAS  Google Scholar 

  78. Stathakis P, Fitzgerald M, Matthias LJ, Chesterman CN, Hogg PJ. Generation of angiostatin by reduction and proteolysis of plasmin. Catalysis by a plasmin reductase secreted by cultured cells. J Biol Chem 1997;272(33):20641–5.

    PubMed  CAS  Google Scholar 

  79. Soff GA, Wang H, Cundiff DL, et al. In vivo generation of angiostatin isoforms by administration of a plasminogen activator and a free sulfhydryl donor: a phase I study of an angiostatic cocktail of tissue plasminogen activator and mesna. Clin Cancer Res 2005;11(17):6218–25.

    PubMed  CAS  Google Scholar 

  80. Kwaan HC. Double hazard of thrombophilia and bleeding in leukemia. Hematology Am Soc Hematol Educ Program 2007;2007:151–7.

    Google Scholar 

  81. Tallman MS, Kwaan HC. Intravascular clotting activation and bleeding in patients with hematologic malignancies. Rev Clin Exp Hematol 2004;8(1):E1.

    PubMed  Google Scholar 

  82. Kwaan HC, Wang J, Boggio LN. Abnormalities in hemostasis in acute promyelocytic leukemia. Hematol Oncol 2002;20(1):33–41.

    PubMed  Google Scholar 

  83. Kwaan HC, Wang J, Weiss I. Expression of receptors for plasminogen activators on endothelial cell surface depends on their origin. J Thromb Haemost 2004;2(2):306–12.

    PubMed  CAS  Google Scholar 

  84. Tapiovaara H, Alitalo R, Stephens R, Myohanen H, Ruutu T, Vaheri A. Abundant urokinase activity on the surface of mononuclear cells from blood and bone marrow of acute leukemia patients. Blood 1993;82(3):914–9.

    PubMed  CAS  Google Scholar 

  85. Tapiovaara H, Matikainen S, Hurme M, Vaheri A. Induction of differentiation of promyelocytic NB4 cells by retinoic acid is associated with rapid increase in urokinase activity subsequently downregulated by production of inhibitors. Blood 1994;83(7):1883–91.

    PubMed  CAS  Google Scholar 

  86. Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood 1993;82(11):3241–9.

    PubMed  CAS  Google Scholar 

  87. Tallman MS, Abutalib SA, Altman JK. The double hazard of thrombophilia and bleeding in acute promyelocytic leukemia. Semin Thromb Hemost 2007;33(4):330–8.

    PubMed  Google Scholar 

  88. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002;100(13):4298–302.

    PubMed  CAS  Google Scholar 

  89. Fenaux P, Chastang C, Chevret S, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1999;94(4):1192–200.

    PubMed  CAS  Google Scholar 

  90. Sanz MA, Martin G, Gonzalez M, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004;103(4):1237–43.

    PubMed  CAS  Google Scholar 

  91. Federici AB, Falanga A, Lattuada A, Di Rocco N, Barbui T, Mannucci PM. Proteolysis of von Willebrand factor is decreased in acute promyelocytic leukaemia by treatment with all-trans-retinoic acid. Br J Haematol 1996;92(3):733–9.

    PubMed  CAS  Google Scholar 

  92. Look MP, van Putten WL, Duffy MJ, et al. Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 2002;94(2):116–28.

    PubMed  CAS  Google Scholar 

  93. Harbeck N, Kates RE, Schmitt M. Clinical relevance of invasion factors urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 for individualized therapy decisions in primary breast cancer is greatest when used in combination. J Clin Oncol 2002;20(4):1000–7.

    PubMed  Google Scholar 

  94. Harbeck N, Kates RE, Look MP, et al. Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (n = 3424). Cancer Res 2002;62(16):4617–22.

    PubMed  CAS  Google Scholar 

  95. Foekens JA, Look MP, Peters HA, van Putten WL, Portengen H, Klijn JG. Urokinase-type plasminogen activator and its inhibitor PAI-1: predictors of poor response to tamoxifen therapy in recurrent breast cancer. J Natl Cancer Inst 1995;87(10):751–6.

    PubMed  CAS  Google Scholar 

  96. Hataji O, Taguchi O, Gabazza EC, et al. Increased circulating levels of thrombin-activatable fibrinolysis inhibitor in lung cancer patients. Am J Hematol 2004;76(3):214–9.

    PubMed  CAS  Google Scholar 

  97. Janicke F, Prechtl A, Thomssen C, Harbeck N, Meisner C, Untch M, Sweep CG, Selbmann HK, Graeff H, Schmitt M. Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1. J Natl Cancer Inst 2001;93:913–20.

    PubMed  CAS  Google Scholar 

  98. Foekens JA, Buessecker F, Peters HA, Krainick U, van Putten WL, Look MP, Klijn JG, Kramer MD. Plasminogen activator inhibitor-2: Prognostic relevance in 1012 patients with primary breast cancer. Cancer Res 1995;55:1423–7.

    PubMed  CAS  Google Scholar 

  99. Sternlicht MD, Dunning AM, Moore DH, Pharoah PD, Ginzinger DG, Chin K, Gray JW, Waldman FM, Ponder BA, Werb Z. Prognostic value of pai1 in invasive breast cancer: Evidence that tumor-specific factors are more important than genetic variation in regulating pai1 expression. Cancer Epidemiol Biomarkers Prev 2006;15:2107–14.

    PubMed  CAS  Google Scholar 

  100. Grondahl-Hansen J, Peters HA, van Putten WL, Look MP, Pappot H, Ronne E, Dano K, Klijn JG, Brunner N, Foekens JA. Prognostic significance of the receptor for urokinase plasminogen activator in breast cancer. Clin Cancer Res 1995;1:1079–87.

    PubMed  CAS  Google Scholar 

  101. Duffy MJ, Duggan C, Mulcahy HE, McDermott EW, O’Higgins NJ. Urokinase plasminogen activator: A prognostic marker in breast cancer including patients with axillary node-negative disease. Clin Chem 1998;44:1177–83.

    PubMed  CAS  Google Scholar 

  102. Demirkan B, Ozcan MA, Glu AA, Yuksel F, Undar B, Alakavuklar M. The effect of anthracycline-based (epirubicin) adjuvant chemotherapy on plasma tafi and pai-1 levels in operable breast cancer. Clin Appl Thromb Hemost 2006;12:9–14.

    PubMed  CAS  Google Scholar 

  103. Wojtukiewicz MZ, Sierko E, Zacharski LR, Zimnoch L, Kudryk B, Kisiel W. Tissue factor-dependent coagulation activation and impaired fibrinolysis in situ in gastric cancer. Semin Thromb Hemost 2003;29:291–300.

    PubMed  CAS  Google Scholar 

  104. Heiss MM, Babic R, Allgayer H, Gruetzner KU, Jauch KW, Loehrs U, Schildberg FW. Tumor-associated proteolysis and prognosis: New functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system. J Clin Oncol 1995;13:2084–93.

    PubMed  CAS  Google Scholar 

  105. Nekarda H, Schmitt M, Ulm K, Wenninger A, Vogelsang H, Becker K, Roder JD, Fink U, Siewert JR. Prognostic impact of urokinase-type plasminogen activator and its inhibitor pai-1 in completely resected gastric cancer. Cancer Res 1994;54:2900–907.

    PubMed  CAS  Google Scholar 

  106. Cho JY, Chung HC, Noh SH, Roh JK, Min JS, Kim BS. High level of urokinase-type plasminogen activator is a new prognostic marker in patients with gastric carcinoma. Cancer 1997;79:878–83.

    PubMed  CAS  Google Scholar 

  107. Beyer BC, Heiss MM, Simon EH, Gruetzner KU, Babic R, Jauch KW, Schildberg FW, Allgayer H. Urokinase system expression in gastric carcinoma: Prognostic impact in an independent patient series and first evidence of predictive value in preoperative biopsy and intestinal metaplasia specimens. Cancer 2006;106:1026–35.

    PubMed  CAS  Google Scholar 

  108. Luebke T, Baldus SE, Spieker D, Grass G, Bollschweiler E, Schneider PM, Thiele J, Dienes HP, Hoelscher AH, Moenig SP. Is the urokinase-type plasminogen activator system a reliable prognostic factor in gastric cancer? Int J Biol Markers 2006;21:162–9.

    PubMed  CAS  Google Scholar 

  109. Skelly MM, Troy A, Duffy MJ, Mulcahy HE, Duggan C, Connell TG, O’Donoghue DP, Sheahan K. Urokinase-type plasminogen activator in colorectal cancer: Relationship with clinicopathological features and patient outcome. Clin Cancer Res 1997;3:1837–40.

    PubMed  CAS  Google Scholar 

  110. Mulcahy HE, Duffy MJ, Gibbons D, McCarthy P, Parfrey NA, O’Donoghue DP, Sheahan K. Urokinase-type plasminogen activator and outcome in dukes’ b colorectal cancer. Lancet 1994;344:583–4.

    PubMed  CAS  Google Scholar 

  111. Yang JL, Seetoo D, Wang Y, Ranson M, Berney CR, Ham JM, Russell PJ, Crowe PJ. Urokinase-type plasminogen activator and its receptor in colorectal cancer: Independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets. Int J Cancer 2000;89:431–9.

    PubMed  CAS  Google Scholar 

  112. Ganesh S, Sier CF, Heerding MM, Griffioen G, Lamers CB, Verspaget HW. Urokinase receptor and colorectal cancer survival. Lancet 1994;344:401–2.

    PubMed  CAS  Google Scholar 

  113. Stephens RW, Nielsen HJ, Christensen IJ, Thorlacius-Ussing O, Sorensen S, Dano K, Brunner N. Plasma urokinase receptor levels in patients with colorectal cancer: Relationship to prognosis. J Natl Cancer Inst 1999;91:869–74.

    PubMed  CAS  Google Scholar 

  114. Kockar C, Kockar O, Ozturk M, Dagli M, Bavbek N, Kosar A. Global fibrinolytic capacity increased exponentially in metastatic colorectal cancer. Clin Appl Thromb Hemost 2005;11:227–30.

    PubMed  CAS  Google Scholar 

  115. Sciacca FL, Ciusani E, Silvani A, Corsini E, Frigerio S, Pogliani S, Parati E, Croci D, Boiardi A, Salmaggi A. Genetic and plasma markers of venous thromboembolism in patients with high grade glioma. Clin Cancer Res 2004;10:1312–7.

    PubMed  CAS  Google Scholar 

  116. Landau BJ, Kwaan HC, Verrusio EN, Brem SS. Elevated levels of urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 in malignant human brain tumors. Cancer Res 1994;54:1105–8.

    PubMed  CAS  Google Scholar 

  117. Hsu DW, Efird JT, Hedley-Whyte ET. Prognostic role of urokinase-type plasminogen activator in human gliomas. Am J Pathol 1995;147:114–123.

    PubMed  CAS  Google Scholar 

  118. Kwaan HC, Lo R, McFadzean AJ. Antifibrinolytic activity in primary carcinoma of the liver. Clin Sci 1959;18:251–61.

    PubMed  CAS  Google Scholar 

  119. De Petro G, Tavian D, Copeta A, Portolani N, Giulini SM, Barlati S. Expression of urokinase-type plasminogen activator (u-pa), u-pa receptor, and tissue-type pa messenger rnas in human hepatocellular carcinoma. Cancer Res 1998;58:214–9.

    PubMed  Google Scholar 

  120. Pavey SJ, Hawson GA, Marsh NA. Impact of the fibrinolytic enzyme system on prognosis and survival associated with non-small cell lung carcinoma. Blood Coagul Fibrinolysis 2001;12:51–8.

    PubMed  CAS  Google Scholar 

  121. Miyake H, Hara I, Yamanaka K, Gohji K, Arakawa S, Kamidono S. Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer. Prostate 1999;39:123–9.

    PubMed  CAS  Google Scholar 

  122. Hienert G, Kirchheimer JC, Pfluger H, Binder BR. Urokinase-type plasminogen activator as a marker for the formation of distant metastases in prostatic carcinomas. J Urol 1988;140:1466–9.

    PubMed  CAS  Google Scholar 

  123. Shariat SF, Roehrborn CG, McConnell JD, Park S, Alam N, Wheeler TM, Slawin KM. Association of the circulating levels of the urokinase system of plasminogen activation with the presence of prostate cancer and invasion, progression, and metastasis. J Clin Oncol 2007;25:349–55.

    PubMed  CAS  Google Scholar 

  124. Torzewski M, Sarbia M, Verreet P, Dutkowski P, Heep H, Willers R, Gabbert HE. Prognostic significance of urokinase-type plasminogen activator expression in squamous cell carcinomas of the esophagus. Clin Cancer Res 1997;3:2263–8.

    PubMed  CAS  Google Scholar 

  125. Nekarda H, Schlegel P, Schmitt M, Stark M, Mueller JD, Fink U, Siewert JR. Strong prognostic impact of tumor-associated urokinase-type plasminogen activator in completely resected adenocarcinoma of the esophagus. Clin Cancer Res 1998;4:1755–63.

    PubMed  CAS  Google Scholar 

  126. Wojtukiewicz MZ, Sierko E, Zacharski LR, Rozanska-Kudelska M, Zimnoch L. Occurrence of components of fibrinolytic pathways in situ in laryngeal cancer. Semin Thromb Hemost 2003;29:317–20.

    PubMed  CAS  Google Scholar 

  127. Kuhn W, Schmalfeldt B, Reuning U, Pache L, Berger U, Ulm K, Harbeck N, Spathe K, Dettmar P, Hofler H, Janicke F, Schmitt M, Graeff H. Prognostic significance of urokinase (upa) and its inhibitor pai-1 for survival in advanced ovarian carcinoma stage figo iiic. Br J Cancer 1999;79:1746–51.

    PubMed  CAS  Google Scholar 

  128. Konecny G, Untch M, Pihan A, Kimmig R, Gropp M, Stieber P, Hepp H, Slamon D, Pegram M: Association of urokinase-type plasminogen activator and its inhibitor with disease progression and prognosis in ovarian cancer. Clin Cancer Res 2001;7:1743–9.

    PubMed  CAS  Google Scholar 

  129. Kwaan HC, Radosevich JA, Xu CG, Lastre C. Tissue plasminogen activator and inhibitors of fibrinolysis in malignant melanoma. Tumour Biol 1988;9:301–6.

    PubMed  CAS  Google Scholar 

  130. Tecimer C, Doering DL, Goldsmith LJ, Meyer JS, Abdulhay G, Wittliff JL. Clinical relevance of urokinase-type plasminogen activator, its receptor, and its inhibitor type 1 in endometrial cancer. Gynecol Oncol 2001;80:48–55.

    PubMed  CAS  Google Scholar 

  131. Kobayashi H, Fujishiro S, Terao T. Impact of urokinase-type plasminogen activator and its inhibitor type 1 on prognosis in cervical cancer of the uterus. Cancer Res 1994;54:6539–48.

    PubMed  CAS  Google Scholar 

  132. Hofmann R, Lehmer A, Buresch M, Hartung R, Ulm K. Clinical relevance of urokinase plasminogen activator, its receptor, and its inhibitor in patients with renal cell carcinoma. Cancer 1996;78:487–92.

    PubMed  CAS  Google Scholar 

  133. Ohba K, Miyata Y, Kanda S, Koga S, Hayashi T, Kanetake H. Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and plasminogen activator inhibitors in patients with renal cell carcinoma: Correlation with tumor associated macrophage and prognosis. J Urol 2005;174:461–5.

    PubMed  Google Scholar 

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  1. Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Hau C. Kwaan

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    Kwaan, H.C., McMahon, B. (2009). The Role of Plasminogen-Plasmin System in Cancer. In: Kwaan, H., Green, D. (eds) Coagulation in Cancer. Cancer Treatment and Research, vol 148. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-79962-9_4

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