Plasminogen Activator System and its Clinical Significance in Patients with a Malignant Disease
Authors:
J. Halámková 1; I. Kiss 1; J. Tomášek 1; Z. Pavlovský 2; Z. Čech 3; Š. Tuček 1; L. Hanáková 4; M. Moulis 2; M. Penka 3
Authors‘ workplace:
Klinika komplexní onkologické péče, Masarykův onkologický ústav a LF MU Brno
1; Patologicko-anatomický ústav FN Brno a LF MU
2; Oddělení klinické hematologie FN Brno a LF MU
3; Interní hematoonkologická klinika FN Brno a LF MU
4
Published in:
Klin Onkol 2011; 24(6): 418-423
Category:
Reviews
Overview
Urokinase (uPA) plays an essential role in the activation of plasminogen to plasmin, a serine protease participating in the activation of matrixmetaloproteinases, latent elastases, growth factors and cytokines involved in the degradation of extracellular matrix elements. Together with its receptor (uPAR), tissue activator (tPA) and urokinase inhibitors (PAI-1, PAI-2, PAI-3 and protease nexin), it forms the plasminogen activator system (PAS), a component of metastatic cascade importantly contributing to the invasive growth and angiogenesis of malignant tumours. Plasminogen activator inhibitor 1 inhibits uPA-dependent invasiveness of some cancer cell lines. The vitronectin-PAI-1 complex inhibits migration of smooth muscle cells by binding αvβ3 integrin to vitronectin. PAI-1 or its deficiency interferes with signalling pathways such as PI3K/Akt and JAK/STAT and it is included in the processes of maintaining the integrity of the endothelial cells and thereby regulation of cell death. PAI-1 affects apoptosis by reducing cell adhesion and functioning of intracellular signalling pathways. The individual components of PAS undoubtedly play an important role in angiogenesis and metastasising of malignant tumours. In the near future, results of published studies with various types of cancer could be reflected in diagnostic and therapeutic algorithms and, at the same time, could serve as the goal for targeted therapies.
Key words:
plasminogen activators – U-PA – U-PA receptor – PAI-1 – PAI-2
This study was supported by the following research programme of the Ministry of Health of the Czech Republic: FUNDIN MO0MOU2005.
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.
Submitted:
3. 4. 2011
Accepted:
20. 9. 2011
Sources
1. Brummel-Ziedins K, Orfeo T, Swords Jenny N et al. Blood coagulation and fibrinolysis. In: Greer JP, Foerster J, Rodgers JM et al (eds). Wintrobe’s Clinical Hematology. 12th ed. Baltimore: Lippincott Wiliams & Wilkins 2009: 528–619.
2. Schmitt M, Harbeck N, Thomssen C et al. Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target therapy. Thromb Haemost 1997; 78: 285–296.
3. Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 2004; 10(1): 39–49.
4. Pyke C, Kristensen P, Ralfkiaer E et al. The plasminogen activation system in human colon cancer: messenger RNA for the inhibitor PAI-1 is located in endothelial cells in tumor stroma. Cancer Res 1991; 51(15): 4067–4071.
5. Fay WP, Shapiro AD, Shih JL et al. Brief report: complete deficiency of plasminogen-activator inhibitor type 1 due to a frame-shift mutation. N Engl J Med 1992; 327(24): 1729–1733.
6. Carmeliet P, Stassen JM, Schoonjans L et al. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effect on haemostasis, thrombosis and thrombolysis. J Clin Invest 1993; 92(6): 2756–2760.
7. Hill SA, Shaughnessy SG, Joshua P et al. Differential mechanisms targeting type 1 plasminogen activator inhibitor and vitronectin into the storage granules of a human megakaryocytic cell line. Blood 1996; 87(12): 5061–5073.
8. Stefansson S, Peticlerc E, Wong MK et al. Inhibition of angiogenesis in vivo by plasminogen activator inhibitor-1. J Biol Chem 2001; 276(11): 8135–8141.
9. Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature 1996; 383(6599): 441–443.
10. Ganesh S, Sier CF, Heerding MM et al. Urokinase receptor and colorectal cancer survival. Lancet 1994; 344(8919): 401–402.
11. Verspaget HW, Sier CF, Ganesh S et al. Prognostic value of plasminogen activators and theirs inhibitors in colorectal cancer. Eur J Cancer 1995; 31A(7–8): 1105–1109.
12. Mignatti P, Rifkin DB. Plasminogen activators and matrix metalloproteinases in angiogenesis. Enzyme Protein 1996; 49(1–3): 117–137.
13. Resnati M, Guttinger M, Valcamonica S et al. Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect. EMBO J 1996; 15(7): 1572–1582.
14. Busso N, Masur SK, Lazega D et al. Induction of cell migration by pro-urokinase binding to its receptor: possible mechanism for signal transduction in human epitelial cells. J Cell Biol 1994; 126(1): 259–270.
15. Nguyen DH, Hussaini IM, Gonias SL. Binding of urokinase-type plasminogen activator to its receptor in MCF-7 cells activates extracellular signal-regulated kinase 1 and 2 which is required for increased cellular motility. J Biol Chem 1998; 273(14): 8502–8507.
16. Dumler I, Weis A, Mayboroda OA et al. The Jak/Stat pathway and urokinase receptor signaling in human aortic vascular smooth muscle cells. J Biol Chem 1998; 273(1): 315–321.
17. Durand MK, Bødker JS, Christensen A et al. Plasminogen activator inhibitor-1 and tumour growth, invasion and metastasis. Tromb Haemost 2004; 91(3): 439–449.
18. Prager GW, Breuss JM, Steurer S et al. Vascular endothelial growth factor receptor-2-induced initial endothelial cell migration depends on the presence of the urokinase receptor. Circ Res 2004; 94(12): 1562–1570.
19. Jänicke F, Schmitt M, Ulm K et al. Urokinase-type plasminogen activator antigen and early relapse in breast cancer. Lancet 1989; 2(8670): 1049.
20. Duffy MJ, O’Grady P, Devaney D et al. Urokinase-plasminogen activator, a marker for aggressive breast carcinomas. Preliminary report. Cancer 1988; 62(3): 531–533.
21. Jänicke F, Schmitt M, Haftner R et al. Urokinase-type plasminogen activator (uPA) antigen is a predictor of early relapse in breast cancer. Fibrinolysis 1990; 4: 69–78.
22. Duggan C, Maguire T, McDermott E et al. Urokinase plasminogen activator and urokinase plasminogen activator receptor in breast cancer. Int J Cancer 1995; 61(5): 597–600.
23. Foekens JA, Buessecker F, Peters HA et al. Plasminogen activator inhibitor 2: prognostic relevance in 1012 patients with primary breast cancer. Cancer Res 1995; 55(7): 1423–1427.
24. Foekens JA, Look MP, Peters HA et al. Urokinase-typ 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): 751–756.
25. 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): 116–128.
26. Kuhn W, Pache L, SchmalfeldT B et al. Urokinase (uPA) and PAI-1 predict survival in advanced ovarian cancer patients (FIGO III) after radical surgery and platinum-based chemotherapy. Gynecol Oncol 1994; 55(1): 401–409.
27. Fredstorp-Lidebring M, Bendahl PO, Brünner N et al. Urokinase plasminogen activator and its inhibitor, PAI-1, in association with progression-free survival in early stage endometrial cancer. Eur J Cancer 2001; 37(18): 2339–2348.
28. Kobayashi H, Fujishiro S, Terao T et al. Impact of urokinase-type plasminogen activator and its inhibitor type 1 on prognosis in cervical cancer of uterus. Cancer Res 1994; 54(24): 6539–6548.
29. Gleeson N, Gonsalves R, Bonnar J et al. Uterine fibrinolytic enzymes in endometrial cancer. Eur J Gynaecol Oncol 1993; 14(5): 369–373.
30. Hasui Y, Marutsuka K, Asada Y et al. Prognostic value of urokinase-type plasminogen activator in patients with superficial bladder cancer. Urology 1996; 47(1): 34–37.
31. Hofmann R, Lehmer A, Buresch M et al. Clinical relevance of urokinase plasminogen activator, its receptor, and its inhibitor in patients with renal cell carcinoma. Cancer 1996; 78(3): 487–492.
32. Ahmad A, Kong D, Sarkar SH et al. Inactivation of uPA and its receptor uPAR by 3,3‘-diindolylmethane (DIM) leads to the inhibition of prostate cancer cell growth and migration. J Cell Biochem 2009; 107(3): 516–527.
33. Xue A, Scarlett CJ, Jackson CJ et al. Prognostic significance of growth factors and the urokinase-type plasminogen activator system in pancreatic ductal adenocarcinoma. Pancreas 2008; 36(2): 160–167.
34. Nomiya T, Nemoto K, Miyachi H et al. Significance of plasminogen-activation system in the formation of macroscopic types and invasion in esophageal carcinoma. Anticancer Res 2002; 22(5): 2913–2916.
35. Kaneko T, Konno H, Baba M et al. Urokinase-type plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer. Cancer Sci 2003; 94(1): 43–49.
36. Hundsdorfer B, Zeilhofer HF, Bock KP et al.Tumour-associated urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in normal and neoplastic tissues of patients with squamous cell cancer of the oral cavity - clinical relevance and prognostic value. J Craniomaxillofac Surg 2005; 33(3): 191–196.
37. Hsu DW, Efird JT, Hedley-Whyte ET et al. Prognostic role of urokinase-type plasminogen activator in human gliomas. Am J Pathol 1995; 147(1): 114–123.
38. Pappot H, Pedersen AN, Brünner N et al. The complex between urokinase (uPA) and its type-1 inhibitor (PAI-1) in pulmonary adenocarcinoma: relation to prognosis. Lung Cancer 2006; 51(2): 193–200.
39. Choong PF, Fernö M, Akerman M et al. Urokinase-plasminogen-activator levels and prognosis in 69 soft-tissue sarcomas. Int J Cancer 1996; 69(4): 268–272.
40. Morii T, Yabe H, Morioka H et al. Prognostic relevance of urokinase type plasminogen activator, its receptor and inhibitors in chondrosarcoma. Anticancer Res 2000; 20(5A): 3031–3036.
41. Stephens RW, Nielsen HJ, Christensen IJ et al. Plasma urokinase receptor levels in patients with colorectal cancer: relationship to prognosis. J Natl Cancer Inst 1999; 91(10): 869–874.
42. Ganesh S, Sier CF, Heerding MM et al. Contribution of plasminogen activators and their inhibitors to the survival prognosis of patients with Duke’s stage B and C colorectal cancer. Br J Cancer 1997; 75(12): 1793–1801.
43. Mulcahy HE, Duffy MJ, Gibbons D et al. Urokinase-type plasminogen activator and outcome in Dukes’ B colorectal cancer. Lancet 1994; 344(8922): 583–584.
44. Graziano F, Cascinu S. Prognostic molecular markers for planning adjuvant chemotherapy trials in Dukes’ B colorectal cancer patients: how much evidence is enough? Ann Oncol 2003; 14(7): 1026–1038.
45. Sier CF, Vloedgraven HJ, Ganesh S et al. Inactive urokinase and increased levels of its inhibitor type 1 in colorectal cancer liver metastasis. Gastroenterology 1994; 107(5): 1449–1456.
46. Suzuki S, Hayashi Y, Wang Y et al. Urokinase type plasminogen activator receptor expression in colorectal neoplasms. Gut 1998; 43(6): 798–805.
47. Ganesh S, Sier CF, Griffioen G et al. Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer. Cancer Res 1994; 54(15): 4065–4071.
48. Nekarda H, Siewert JR, Schmitt M et al. Tumour-associated proteolytic factors uPA and PAI-1 and survival in totally resected gastric cancer. Lancet 1994; 343(8889): 117.
49. Zemzoum I, Kates RE, Ross JS et al. Invasion factors uPA/PAI-1 and HER2 status provide independent and complementary information on patient outcome in node-negative breast cancer. J Clin Oncol 2003; 21(6): 1022–1028.
50. Hildenbrand R, Schaaf A, Dorn-Beineke A et al. Tumor stroma is the predominant uPA-, uPAR-, PAI-1-expressing tissue in human breast cancer: prognostic impact. Histol Histopathol 2009; 24(7): 869–877.
51. Sakakibara T, Hibi K, Koike M et al. Plasminogen activator inhibitor-1 as a potential marker for the malignancy of colorectal cancer. Br J Cancer 2005; 93(7): 799–803.
52. Ohba K, Miyata Y, Kanda S et al. 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(2): 461–465.
53. Schmitt M, Wilhelm O, Reuning U et al. The urokinase plasminogen activator system as a novel target for tumour therapy. Fibrinol Proteol 2000; 14: 114–132.
54. Pedersen H, Grøndahl-Hansen J, Francis D et al. Urokinase and plasminogen activator inhibitor type 1 in pulmonary adenocarcinoma. Cancer Res 1994; 54(1): 120–123.
55. Konecny G, Untch M, Pihan A et al. Association of urokinase-type plasminogen activator and its inhibitor with disease progression and prognosis in ovarian cancer. Clin Cancer Res 2001; 7(6): 1743–1749.
56. Waltz DA, Natkin LR, Fujita RM et al. Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin. J Clin Invest 1997; 100(1): 58–67.
57. Deng C, Curriden SA, Wang S et al. Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release? J Cell Biol 1996; 134(6): 1563–1571.
58. Grøndahl-Hansen J, Christensen IJ, RosenquisTC et al. High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res 1993; 53(11): 2513–2521.
59. Jelisavac-Cosic S, Sirotkovic-Skerlev M, Kulic A et al. Prognostic significance of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) in patients with primary invasive ductal breast carcinoma - a 7.5-year follow-up study. Tumori 2011; 97(4): 532–539.
60. Knoop A, Andreasen PA, Andersen JA et al. Prognostic significance of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in primary breast cancer. Br J Cancer 1998; 77(6): 932–940.
61. Ito H, Yonemura Y, Fujita H et al. Prognostic relevance of urokinase-type plasminogen actiator (uPA) and plasminogen activator inhibitor PAI-1 and PAI-2 in gastric cancer. Virchows Arch 1996; 427(5): 487–496.
62. Bouchet C, Spyratos F, Martin PM et al. Prognostic value of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in breast carcinomas. Br J Cancer 1994; 69(2): 398–405.
63. Maeda K, Chung YS, Sawada T et al. Combined evaluation of urokinase-type plasminogen activator and plasminogen activator inhibitor-2 expression in gastric carcinoma. Int J Oncol 1996; 8(3): 499–503.
64. Macaluso M, Montanari M, Marshall CM et al. Cytoplasmic and nuclear interaction between Rb family proteins and PAI-2: a physiological crosstalk in human corneal and conjunctival epithelial cells. Cell Death Differ 2006; 13(9): 1515–1522.
65. Darnell DA, Antalis TM, Johnstone RW et al. Inhibition of retinoblastoma protein degradation by interaction with the serpin plasminogen activator inhibitor 2 via a novel consensus motif. Mol Cell Biol 2003; 23(18): 6520–6532.
66. Sumiyoshi K, Serizawa K, Urano T et al. Plasminogen activator system in human breast cancer. Int J Cancer 1992; 50(3): 345–348.
67. Nagayama M, Sato A, Hayakawa H et al. Plasminogen activators and their inhibitors in non-small cell lung cancer. Low content of type 2 plasminogen activator inhibitor associated with tumor dissemination. Cancer 1994; 73(5): 1398–1405.
68. Smith R, Xue A, Gill A et al. High expression of plasminogen activator inhibitor-2 (PAI-2) is a predictor of improved survival in patients with pancreatic adenocarcinoma. World J Surg 2007; 31(3): 493–502.
69. Nordengren J, Fredstorp Lidebring M, Bendahl PO et al. High tumor tissue concentration of plasminogen activator inhibitor 2 (PAI-2) is an independent marker for shorter progression-free survival in patients with early stage endometrial cancer. Int J Cancer 2002; 97(3): 379–385.
70. Kammori M, Kaminishi M, Kobayashi K et al. Immunohistochemical analysis of PAI-2 (plasminogen activator inhibitor type 2) and p53 protein in early gastric cancer patients with recurrence: a preliminary report. Jpn J Clin Oncol 1999; 29(4): 187–191.
71. Minisini AM, Fabbro D, Di Loreto C et al. Markers of the uPA system and common prognostic factors in breast cancer. Am J Clin Pathol 2007; 128(1): 112–117.
72. Dublin E, Hanby A, Patel NK et al. Immunohistochemical expression of uPA, uPAR, and PAI-1 in breast carcinoma. Fibroblastic expression has strong associations with tumor pathology. Am J Pathol 2000; 157(4): 1219–1227.
73. Cai Z, Li YF, Liu FY et al. Expression and clinical significance of uPA and PAI-1 in epithelial ovarian cancer. Ai Zheng 2007; 26(3): 312–317.
74. Horvatić Herceg G, Herceg D, Kralik M et al. Urokinase-type plasminogen activator and its inhibitor in thyroid neoplasms: a cytosol study. Wien Klin Wochenschr 2006; 118(19–20): 601–609.
75. Muracciole X, Romain S, Dufour H et al. PAI-1 and EGFR expression in adult glioma tumors: toward a molecular prognostic classification. Int J Radiat Oncol 2002; 52(3): 592–598.
76. Itoh T, Hayashi Y, Kanamaru T et al. Clinical significance of urokinase-type plasminogen activator activity in hepatocellular carcinoma. J Gastroenterol Hepatol 2000; 15(4): 422–430.
77. Papadopoulou S, Scorilas A, Yotis J et al. Significance of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) expression in human colorectal carcinomas. Tumour Biol 2002; 23(3): 170–178.
78. Cozzi PJ, Wang J, Delprado W et al. Evaluation of urokinase plasminogen activator and its receptor in different grades of human prostate cancer. Hum Pathol 2006; 37(11): 1442–1451.
79. Manders P, Tjan-Heijnen VC, Span PN et al. Complex of urokinase-type plasminogen activator with its type 1 inhibitor predicts poor outcome in 576 patients with lymph node-negative breast carcinoma. Cancer 2004; 101(3): 486–494.
80. Herszényi L, Farinati F, Cardin R et al. Tumor marker utility and prognostic relevance of cathepsin B, cathepsin L, urokinase-type plasminogen activator, plasminogen activator inhibitor type-1, CEA and CA 19-9 in colorectal cancer. BMC Cancer 2008; 10: 194.
81. Foekens JA, Look MP, Peters HA et al. 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): 751–756.
82. Heiss MM, Allgayer H, Gruetzner KU et al. Clinical value of extended biologic staging by bone marrow micrometastases and tumor-associated proteases in gastric cancer. Ann Surg 1997; 226(6): 736–745.
83. de Bruin PA, Verspaget HW, Griffioen G et al. Plasminogen activator activity and composition in human colorectal carcinomas. Fibrinolysis 1987; 1: 57–62.
84. de Bruin PA, Griffioen G, Verspaget HW et al. Plasminogen activators and tumor development in the human colon: activity levels in normal mucosa, adenomatous polyps, and adenocarcinomas. Cancer Res 1987; 47(17): 4654–4657.
85. Mytnik M, Stasko J. D-dimer, plasminogen activator inhibitor-1, prothrombin fragments and protein C – role in prothrombotic state of colorectal cancer. Neoplasma 2011; 58(3): 235–238.
86. Halamkova J, Kiss I, Pavlovsky Z et al. Clinical significance of the plasminogen activator system in relation to grade of tumor and treatment response in colorectal carcinoma patients. Neoplasma 2011; 58(5): 377–385.
87. Seetoo DQ, Crowe PJ, Russell PJ et al. Quantitative expression of protein markers of plasminogen activation system in prognosis of colorectal cancer. J Surg Oncol 2003; 82(3): 184–193.
88. Sato T, Nishimura G, Yonemura Y et al. Association of immunohistochemical detection of urokinase-type plasminogen activator with metastasis and prognosis in colorectal cancer. Oncology 1995; 52(4): 347–352.
89. Langenskiöld M, Holmdahl L, Angenete E et al. Differential prognostic impact of uPA and PAI-1 in colon and rectal cancer. Tumour Biol 2009; 30(4): 210–220.
90. Leik CE, Su EJ, Nambi P et al. Effect of pharmacologic plasminogen activator inhibitor-1 inhibition on cell motility and tumor angiogenesis. J Thromb Haemost 2006; 4(12): 2710–2715.
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