Tumorassoziierte Prognosefaktoren der Plasminogenaktivator-Familie

Zusammenfassung

Proteolysefaktoren aus der Plasminogenaktivator-Familie (Plasmin, t-PA, u-PA, u-PAR, PAI-1, PAI-2), die an Blutgerinnung und Abbau von Blutgerinnseln beteiligt sind, kommen in gesunden und Krebszellen (z. B. der Niere, Lunge, Leber, Brust, Prostata, des Ovars, Gehirns und Magen-Darmtrakts) vor und sind dort an Neuronalentwicklung, Blutgefäßausbreitung und Wundheilung sowie der Plazentabildung und Embryonalentwicklung beteiligt. Diese Proteolysefaktoren sind im malignen Gewebe oft in größerer Menge als im Normalgewebe der befallenen Organe anzutreffen. Bei Brustkrebspatientinnen geht ein hoher Gehalt des Plasminogenaktivators u-PA, des Plasminogenaktivator-Inhibitors PAI-1 und des u-PA-Rezeptors u-PAR (CD87) im Tumorgewebe mit erhöhter Tumoraggressivität und schlechter Prognose einher, ein erhöhter Gehalt des Plasminogenaktivators t-PA und des Inhibitors PAI-2 jedoch mit einer guten Prognose. Zur klinisch relevanten Bestimmung dieser Proteolysefaktoren im Tumorgewebeextrakt werden enzymimmunometrische ELISA-Tests empfohlen. Die enzymatische und zymographische Aktivität dieser Faktoren wird nur im Rahmen experimenteller, vorklinischer Untersuchungen bestimmt.

Summary

Proteolytic factors belonging to the plasminogen activator family (plasmin, u-PA, t-PA, u-PAR, PAI-1, and PAI-2), which usually are involved in blood clotting and degradation of blood clots, are also present in healthy and diseased tissue of the kidney, lung, liver, gastro-intestinal tract, breast, prostate, ovary, and brain. These factors are engaged in brain development, angiogenesis and vascular invasion, wound healing as well as in placenta development and embryogenesis. Plasminogen activators u-PA and t-PA, their inhibitors PAI-1 and PAI-2, and the u-PA-receptor (u-PAR, CD87) are often elevated in solid malignant tumour tissues compared to their normal counterparts. In breast cancer patients, an elevated tumour tissue extract antigen content of u-PA, PAI-1, and u-PAR is associated with increased tumour aggressiveness and poor prognosis; in contrary, an elevated content of t-PA and PAI-2 indicates a favourable prognosis. For clinical relevant determination of these proteolytic factors in tumour tissue extracts, only enzymo-immunometric tests (ELISA) are recommended. Enzymometric and enzymographic tests are actually conducted only in an experimental, preclinical context.

Schlüsselwörter

Plasminogenaktivator - chromogene Substrate - Plasminogenaktivator-Inhibitor - Protease - Brustkrebs - Plasmin - u-PA - t-PA - PAI-1 - u-PAR

Keywords

Plasminogen activator - chromogenic substrates - plasminogen activator inhibitor - breast cancer - protease - plasmin - u-PA - t-PA - PAI-1 - u-PAR

• Literatur

• 1 Almholt K, Nielsen BS, Frandsen TL. et al. Metastasis of transgenic breast cancer in plasminogen activator inhibitor-1 gene-deficient mice. Oncogene 2003; 22: 4389-97.
• 2 Andreasen PA, Kjøller L, Christensen L. et al. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997; 72: 1-22.
• 3 Andreasen PA, Petersen LC, Danø K. Diversity in catalytic properties of single-chain and two-chain tissue-type plasminogen activator. Fibrinolysis 1991; 5: 207-15.
• 4 Andreasen PA, Egelund R, Petersen HH. The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci 2000; 57: 25-40.
• 5 Appella E, Robinson EA, Ullrich SJ. et al. The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J Biol Chem 1987; 262: 4437-40.
• 6 Astedt B, Holmberg L. Immunological identity of urokinase and ovarian carcinoma plasminogen activator released in tissue culture. Nature 1976; 261: 595-7.
• 7 Astedt B, Lundgren E, Roos G. et al. Release of various molecular forms of plasminogen activators during culture of human ovarian tumours. Thromb Res 1978; 13: 1031-7.
• 8 Astedt B. Adjuvant treatment of ovarian carcinoma with tranexamic acid. J Clin Pathol Suppl (R Coll Pathol) 1980; 14: 74-6.
• 9 Bajou K, Noel A, Gerard RD. et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 1998; 4: 923-8.
• 10 Behrendt N, Ploug M, Patthy L. et al. The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator. J Biol Chem 1991; 266: 7842-7.
• 11 Behrendt N, Rønne E, Danø K. Domain interplay in the urokinase receptor: requirement for the third domain in high affinity ligand binding and demonstration of ligand contact sites in distinct receptor domains. J Biol Chem 1996; 271: 22885-94.
• 12 Benraad TJ, Geurts-Moespot J, Grondahl-Hansen J. et al. Immunoassays (ELISA) of urokinase-type plasminogen activator (uPA): report of an EORTC/BIOMED-1 workshop. Eur J Cancer 1996; 32A: 1371-81.
• 13 Birchmeier C, Gherardi E. Developmental roles of HGF:SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol 1998; 8: 404-10.
• 14 Borstnar S, Vrhovec I, Svetic B. et al. Prognostic value of the urokinase-type plasminogen activator, and its inhibitors and receptor in breast cancer patients. Clin Breast Cancer 2002; 3: 138-46.
• 15 Brenner B. Haemostatic changes in pregnancy. Thromb Res 2004; 114: 409-14.
• 16 Bugge TH, Lund LR, Kombrinck KK. et al. Reduced metastasis of Polyoma virus middle T antigeninduced mammary cancer in plasminogen-deficient mice. Oncogene 1998; 16: 3097-104.
• 17 Bugge TH, Suh TT, Flick MJ. et al. The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility. J Biol Chem 1995; 270: 16886-94.
• 18 Bürgle M, Sperl S, Stürzebecher J. et al. The urokinase-type plasminogen activator (uPA) system: a new target for tumor therapy. In: Smith HJ, Simons C. (eds). Proteinase and peptidase inhibition: Recent potential targets for drug development. London, New York: Taylor and Francis; 2002: 231-48.
• 19 Chen Y, Kelm RJ, Budd Jr RC. et al. Inhibition of apoptosis and caspase-3 in vascular smooth muscle cells by plasminogen activator inhibitor type-1. J Cell Biochem 2004; 92: 178-88.
• 20 Collen D. On the regulation of fibrinolysis. Thromb Haemost 1980; 43: 77-89.
• 21 Crisp RJ, Knauer DJ, Knauer MF. Roles of the heparin and low density lipid receptor-related protein-binding sites of protease nexin 1 (PN1) in urokinase-PN1 complex catabolism. The PN1 heparin-binding site mediates complex retention and degradation but not cell surface binding or internalization. J Biol Chem 2000; 275: 19628-37.
• 22 Davidson JF, McNicol GP, Frank GL. et al. Plasminogen-activator-producing tumour. Br Med J 1969; 1: 88-91.
• 23 de Witte H, Pappot H, Brunner N. et al. ELISA for complexes between urokinase-type plasminogen activator and its receptor in lung cancer tissue extracts. Int J Cancer 1997; 72: 416-23.
• 24 de Witte H, Sweep F, Brunner N. et al. Complexes between urokinase-type plasminogen activator and its receptor in blood as determined by enzyme-linked immunosorbent assay. Int J Cancer 1998; 77: 236-42.
• 25 de Witte JH, Foekens JA, Brunner N. et al. Prognostic impact of urokinase-type plasminogen activator receptor (uPAR) in cytosols and pellet extracts derived from primary breast tumours. Br J Cancer 2001; 85: 85-92.
• 26 del Rosso M, Dini G, Fibbi G. Receptors for plasminogen activator, urokinase, in normal and Rous sarcoma virus-transformed mouse fibroblasts. Cancer Res 1985; 45: 630-6.
• 27 Deng G, 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: 1563-71.
• 28 Deng G, Royle G, Seiffert D. et al. The PAI-1: vitronectin interaction: two cats in a bag?. Thromb Haemost 1995; 74: 66-70.
• 29 Dickinson JL, Norris BJ, Jensen PH. et al. 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: 163-71.
• 30 Duffy MJ, O’Grady P, Devaney D. et al. Urokinaseplasminogen activator, a marker for aggressive breast carcinomas. Preliminary report. Cancer 1988; 62: 531-3.
• 31 Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 2004; 10: 39-49.
• 32 Durand MK, Bodker JS, Christensen A. et al. Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis. Thromb Haemost 2004; 91: 438-49.
• 33 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: 1423-7.
• 34 Foekens JA, Look MP, Peters HA. et al. Urokinasetype plasminogen activator and its inhibitor PAI-1: predictors of poor response to tamoxifen therapy in recurrent breast cancer. J Natl Cancer Inst 1995; 87: 751-6.
• 35 Foekens JA, Peters HA, Look MP. et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res 2000; 60: 636-43.
• 36 Foekens JA, Schmitt M, van Putten WL. et al. Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients. Cancer Res 1992; 52: 6101-5.
• 37 Foekens JA, Schmitt M, van Putten WL. et al. Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. J Clin Oncol 1994; 12: 1648-58.
• 38 Grebenschikov N, Geurts-Moespot A, de Witte H. et al. A sensitive and robust assay for urokinase and tissue-type plasminogen activators (uPA and tPA) and their inhibitor type I (PAI-1) in breast tumor cytosols. Int J Biol Markers 1997; 12: 6-14.
• 39 Harbeck N, Kates RE, Gauger K. et al. Urokinasetype plasminogen activator (uPA) and its inhibitor PAI-I: novel tumor-derived factors with a high prognostic and predictive impact in breast cancer. Thromb Haemost 2004; 91: 450-6.
• 40 Harbeck N, Kruger A, Sinz S. et al. Clinical relevance of the plasminogen activator inhibitor type 1--a multifaceted proteolytic factor. Onkologie 2001; 24: 238-44.
• 41 Harbeck N, Magdolen V, Diamandis E. et al. Tumor-associated proteolytic factors – Markers tufor tumor invasion and metastasis. In: Ross J, Hortobagyi G. (eds). Molecular Oncology of Breast Cancer. Boston: Jones and Bartlett; 2004: 276-88.
• 42 Heeb MJ, Espana F, Geiger M. et al. Immunological identity of heparin-dependent plasma and urinary protein C inhibitor and plasminogen activator inhibitor-3. J Biol Chem 1987; 262: 15813-6.
• 43 Herijgers N, Vettel U, Schaefer B. et al. Cell surface-bound urokinase-type plasminogen activator facilitates infiltration of freshly isolated granulocytes into fibrin matrix. Immunobiology 1995; 194: 363-75.
• 44 Higazi AA, Ajawi F, Akkawi S. et al. Regulation of the single-chain urokinase-urokinase receptor complex activity by plasminogen and fibrin: novel mechanism of fibrin specificity. Blood 2005; 105: 1021-8.
• 45 Janicke F, Pache L, Schmitt M. et al. Both the cytosols and detergent extracts of breast cancer tissues are suited to evaluate the prognostic impact of the urokinase-type plasminogen activator and its inhibitor, plasminogen activator inhibitor type 1. Cancer Res 1994; 54: 2527-30.
• 46 Janicke F, Prechtl A, Thomssen C. et al. 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.
• 47 Janicke F, Schmitt M, Graeff H. Clinical relevance of the urokinase-type and tissue-type plasminogen activators and of their type 1 inhibitor in breast cancer. Semin Thromb Hemost 1991; 17: 303-12.
• 48 Janicke F, Schmitt M, Pache L. et al. Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 1993; 24: 195-208.
• 49 Janicke F, Schmitt M, Ulm K. et al. Urokinase-type plasminogen activator antigen and early relapse in breast cancer. Lancet 1989; 2: 1049.
• 50 Kanse SM, Chavakis T, Al Fakhri N. et al. Reciprocal regulation of urokinase receptor (CD87)-mediated cell adhesion by plasminogen activator inhibitor-1 and protease nexin-1. J Cell Sci 2004; 117: 477-85
• 51 Kotzsch M, Luther T, Harbeck N. et al. New ELISA for quantitation of human urokinase receptor (CD87) in cancer. Int J Oncol 2000; 17: 827-34.
• 52 Krystosek A, Verrall S, Seeds NW. Plasminogen activator secretion in relation to Schwann cell activities. Int J Dev Neurosci 1988; 6: 483-93.
• 53 Kwaan HC, Wang J, Svoboda K. et al. Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. Br J Cancer 2000; 82: 1702-8.
• 54 Longstaff C, Whitton CM. A proposed reference method for plasminogen activators that enables calculation of enzyme activities in SI units. J Thromb Haemost 2004; 2: 1416-21.
• 55 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: 116-28.
• 56 Luther T, Kotzsch M, Meye A. et al. Identification of a novel urokinase receptor splice variant and its prognostic relevance in breast cancer. Thromb Haemost 2003; 89: 705-17.
• 57 Manders P, Tjan-Heijnen VC, Span PN. et al. The complex between urokinase-type plasminogen activator (uPA) and its type-1 inhibitor (PAI-I) independently predicts response to first-line endocrine therapy in advanced breast cancer. Thromb Haemost 2004; 91: 514-21.
• 58 Marsh NA, Gaffney PJ. The rapid fibrin plate – a method for plasminogen activator assay. Thromb Haemost 1977; 38: 545-51.
• 59 Mignatti P, Rifkin DB. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 1993; 73: 161-95.
• 60 Misheneva VS. Effect of some inhibitors on the urokinase activity of the liver of normal and tumor-bearing animals. Ukr Biokhim Zh 1963; 35: 566-72.
• 61 Morganti M, Mittermayer C, Henze U. et al. Expression of tissue-type plasminogen activator, plasminogen activator inhibitor and von Willebrand factor in the supernatant of endothelial cell cultures in response to the seeding of adenocarcinoma cell line HRT-18. Biomed Pharmacother 1996; 50: 373-5.
• 62 Muehlenweg B, Sperl S, Magdolen V. et al. Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumours. Expert Opin Biol Ther 2001; 1: 683-91.
• 63 Myohanen H, Vaheri A. Regulation and interactions in the activation of cell-associated plasminogen. Cell Mol Life Sci 2004; 61: 2840-58.
• 64 Nelles LP, Schnebli HP. Are proteinase inhibitors potentially useful in tumor therapy?. Invasion Metastasis 1982; 2: 113-24.
• 65 Nijziel MR, Van Oerle R, Hellenbrand D. et al. The prognostic value of the soluble urokinase-type plasminogen activator receptor (s-uPAR) in plasma of breast cancer patients with and without metastatic disease. J Thromb Haemost 2003; 1: 982-6.
• 66 Palumbo JS, Kombrinck KW, Drew AF. et al. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood 2000; 96: 3302-9.
• 67 Pedersen N, Schmitt M, Rønne E. et al. A ligandfree, soluble urokinase receptor is present in the ascitic fluid from patients with ovarian cancer. J Clin Invest 1993; 92: 2160-7.
• 68 Petersen LC, Lund LR, Nielsen LS. et al. Onechain urokinase-type plasminogen activator from human sarcoma cells is a proenzyme with little or no intrinsic activity. J Biol Chem 1988; 263: 11189-95.
• 69 Ploug M, Ellis V, Dano K. Ligand interaction between urokinase-type plasminogen activator and its receptor probed with 8-anilino-1-naphthalenesulfonate. Evidence for a hydrophobic binding site exposed only on the intact receptor. Biochemistry 1994; 33: 8991-7.
• 70 Ploug M, Ostergaard S, Hansen LB. et al. Photoaffinity labeling of the human receptor for urokinase-type plasminogen activator using a decapeptide antagonist. Evidence for a composite ligand-binding site and a short interdomain separation. Biochemistry 1998; 37: 3612-22.
• 71 Ploug M, Rahbek-Nielsen H, Ellis V. et al. Chemical modification of the urokinase-type plasminogen activator and its receptor using tetranitromethane. Evidence for the involvement of specific tyrosine residues in both molecules during receptor-ligand interaction. Biochemistry 1995; 34: 12524-34.
• 72 Ploug M, Kjalke M, Rønne E. et al. Localization of the disulfide bonds in the NH₂-terminal domain of the cellular receptor for human urokinase-type plasminogen activator: a domain structure belonging to a novel superfamily of glycolipid-anchored membrane proteins. J Biol Chem 1993; 268: 17539-46.
• 73 Ploug M, Rønne E, Behrendt N. et al. Cellular receptor for urokinase plasminogen activator: carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidyl inositol. J Biol Chem 1991; 266: 1926-33.
• 74 Pratt CW, Macik BG, Church FC. Protein C inhibitor: purification and proteinase reactivity. Thromb Res 1989; 53: 595-602.
• 75 Pujade-Lauraine E, Lu H, Mirshahi S. et al. The plasminogen-activation system in ovarian tumors. Int J Cancer 1993; 55: 27-31.
• 76 Rakic JM, Maillard C, Jost M. et al. Role of plasminogen activator-plasmin system in tumor angiogenesis. Cell Mol Life Sci 2003; 60: 463-73.
• 77 Reuning U, Magdolen V, Wilhelm O. et al. Multifunctional potential of the plasminogen activation system in tumor invasion and metastasis. Int J Oncol 1998; 13: 893-906.
• 78 Richard B, Arocas V, Guillin MC. et al. Protease nexin-1: a cellular serpin down-regulated by thrombin in rat aortic smooth muscle cells. J Cell Physiol 2004; 201: 138-45.
• 79 Riisbro R, Christensen IJ, Piironen T. et al. Prognostic significance of soluble urokinase plasminogen activator receptor in serum and cytosol of tumor tissue from patients with primary breast cancer. Clin Cancer Res 2002; 8: 1132-41.
• 80 Rijken DC. Plasminogen activators and plasminogen activator inhibitors: biochemical aspects. Bailliéres Clin Haematol 1995; 8: 291-312.
• 81 Roldan AL, Cubellis MV, Masucci MT. et al. Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin-dependent proteolysis. EMBO J 1990; 9: 467-74.
• 82 Romer J, Bugge TH, Pyke C. et al. Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med 1996; 2: 287-92.
• 83 Rossignol P, Ho-Tin-Noe B, Vranckx R. et al. Protease nexin-1 inhibits plasminogen activation-induced apoptosis of adherent cells. J Biol Chem 2004; 279: 10346-56.
• 84 Schmitt M, Harbeck N, Thomssen C. et al. Clinical impact of the plasminogen activation system in tu mor invasion and metastasis: prognostic relevance and target for therapy. Thromb Haemost 2004; 78: 285-96.
• 85 Schmitt M, Janicke F, Graeff H. Tumour-associated fibrinolysis: the prognostic relevance of plasminogen activators uPA and tPA in human breast cancer. Blood Coagul Fibrinol 1990; 1: 695-702.
• 86 Schmitt M, Thomssen C, Ulm K. et al. Time-varying prognostic impact of tumour biological factors urokinase (uPA), PAI-1 and steroid hormone receptor status in primary breast cancer. Br J Cancer 1997; 76: 306-11.
• 87 Schmitt M, Chucholowski N, Goretzki L. et al. Fluorescent probes as tools to assess the receptor for the urokinase-type plasminogen activator (uPA) on tumor cells. Sem Thromb Haemost 1991; 17: 291-302.
• 88 Schmitt M, Sturmheit A, Welk A. et al. Procedures for the quantitative protein determination of urokinase (uPA) and its inhibitor PAI-1 in human breast cancer tissue extracts by ELISA. Breast Cancer Protocols. 2005 im Druck.
• 89 Schmitt M, Wilhelm OG, Reuning U. et al. The urokinase plasminogen activator system as a novel target for tumour therapy. Fibrinol Proteol 2000; 14: 114-32.
• 90 Sier CF, Stephens R, Bizik J. et al. The level of urokinase-type plasminogen activator receptor is increased in serum of ovarian cancer patients. Cancer Res 1998; 58: 1843-9.
• 91 Sperl S, Mueller MM, Wilhelm OG. et al. The uPA/uPA receptor system as a target for tumor therapy. Drug News Perspect 2001; 14: 401-11.
• 92 Steinmetzer T. Synthetic urokinase inhibitors as potential antitumor drugs. IDrugs 2003; 6: 138-46.
• 93 Stump DC, Thienpont M, Collen D. Purification and characterization of a novel inhibitor of urokinase from human urine. Quantitation and preliminary characterization in plasma. J Biol Chem 1986; 261: 12759-66.
• 94 Sweep CG, Geurts-Moespot J, Grebenschikov N. et al. External quality assessment of trans-European multicentre antigen determinations (enzyme-linked immunosorbent assay) of urokinase-type plasminogen activator (uPA) and its type 1 inhibitor (PAI-1) in human breast cancer tissue extracts. Br J Cancer 1998; 78: 1434-41.
• 95 Vassalli JD, Baccino D, Belin D. A cellular binding site for the Mr 55,000 form of the human plasminogen activator, urokinase. J Cell Biol 1985; 100: 86-92.
• 96 Wahlberg K, Høyer-Hansen G, Casslen B. Soluble receptor for urokinase plasminogen activator in both full-length and a cleaved form is present in high concentration in cystic fluid from ovarian cancer. Cancer Res 1998; 58: 3294-8.
• 97 Wakita T, Hayashi T, Nishioka J. et al. Regulation of carcinoma cell invasion by protein C inhibitor whose expression is decreased in renal cell carcinoma. Int J Cancer 2004; 108: 516-23.
• 98 Wu JH, Diamond SL. Fluorogenic fibrinogen and fibrin facilitate macromolecular assembly and dynamic assay of picomolar levels of plasminogen activators under well mixed conditions. Thromb Haemost 1995; 74: 711-7.
• 99 Zacharski LR, Ornstein DL, Gabazza EC. et al. Treatment of malignancy by activation of the plasminogen system. Semin Thromb Hemost 2002; 28: 5-18.
• 100 Zhang ZY, Wang ZY, Dong NZ. et al. A case of deficiency of plasma plasminogen activator inhibitor-1 related to Ala15Thr mutation in its signal peptide. Blood Coagul Fibrinol 2005; 16: 79-84.