Summary
To evaluate the clinical relevance of urokinase-type plasminogen activator (uPA) and its type-1 inhibitor (PAI-1) measured by a recently developed enzyme-linked immunosorbent assay (ELISA), we analysed both components in samples derived from 892 patients with primary breast cancer (median follow-up 99 months). The assays were performed in cytosolic extracts as well as in corresponding detergent extracts of pellets obtained after ultracentrifugation, which was carried out when preparing the cytosolic fractions for routine steroid hormone receptor determination. Statistically significant correlations were found between the cytosolic levels and those determined in the pellet extracts (Spearman correlation coefficient rs = 0.60, P < 0.0001 for uPA and rs = 0.65, P < 0.0001 for PAI-1). Furthermore, strong correlations were found between the levels of both uPA (rs = 0.85, P < 0.0001) and PAI-1 (rs = 0.90, P < 0.0001) in the cytosols and their levels previously measured with ELISAs based on commercial reagents. In both Cox univariate and multivariate analysis, high cytosolic levels of uPA or PAI-1 were significantly associated with increased rates of relapse and death. The levels of uPA and PAI-1 in the pellet extracts also provided prognostic information, although to a lesser extent compared with the cytosolic extracts. The prediction of prognosis on the basis of uPA and PAI-1 assessed by an alternative ELISA once again emphasizes the established prognostic role and usefulness of these parameters in selection of breast cancer patients at high or low risk of recurrence.
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References
Andreasen, P. A., Georg, B., Lund, L. R., Riccio, A. & Stacey, S. N. (1990). Plasminogen activator inhibitors: hormonally regulated serpins. Mol Cell Endocrinol 68: 1–19.
Andreasen, P. A., Kjøller, L., Christensen, L. & Duffy, M. J. (1997). The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 72: 1–22.
Benraad, T. h. J., Geurts-Moespot, J., Grøndahl-Hansen, J., Schmitt, M., Heuvel, JJTM, de Witte, J. H., Foekens, J. A., Leake, R. E., Brünner, N. & Sweep, C. G. J. (1996). Immunoassays (ELISA) of urokinase-type plasminogen activator (uPA): report of an EORTC/BIOMED-1 workshop. Eur J Cancer 32A: 1371–1381.
Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72: 248–254.
Chapman, H. A. (1997). Plasminogen activators, integrins, and the coordinated regulation of cell adhesion and migration. Curr Opin Cell Biol 9: 714–724.
De Witte, H., Pappot, H., Brünner, N., Grøndahl-Hansen, J., Høyer-Hansen, G., Behrendt, N., Guldhammer-Skov, B., Sweep, C. G. J., Benraad, T. h. J. & Danø, K. (1997). ELISA for complexes between urokinase-type plasminogen activator and its receptor in lung cancer tissue extracts. Int J Cancer 72: 416–423.
Danø, K., Andreasen, P. A., Grøndahl-Hansen, J., Kristensen, P., Nielsen, L. S. & Skriver, L. (1985). Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 44: 139–266.
Danø, K., Behrendt, N., Brünner, N., Ellis, V., Ploug, M. & Pyke, C. (1994). The urokinase receptor: protein structure and role in plasminogen activation and cancer invasion. Fibrinolysis 8(suppl. 1): 189–203.
Duffy, M. J. (1992). The role of proteolytic enzymes in cancer invasion and metastasis. Clin Exp Metastasis 10: 145–155.
Duffy, M. J. (1996). Proteases as prognostic markers in cancer. Clin Cancer Res 2: 613–618.
Duffy, M. J., Reilly, D., O’Sullivan, C., O’Higgins, N., Fennelly, J. J. & Andreasen, P. A. (1990). Urokinase plasminogen activator, a new and independent prognostic marker in breast cancer. Cancer Res 50: 6827–6929.
EORTC Breast Cancer Cooperative Group (1980). Revision of the standards for the assessment of hormone receptors in human breast cancer; report of the second EORTC workshop, held on 16–17 March 1979, in The Netherlands Cancer Institute. Eur J Cancer 16: 1513–1515.
Fernö, M., Bendahl, P-O, Borg, Å, Brundell, J., Hirschberg, L., Olsson, H. & Killander, D. (1996). Urokinase plasminogen activator, a strong independent prognostic factor in breast cancer, analysed in steroid receptor cytosols with a luminometric immunoassay. Eur J Cancer 32A: 793–801.
Foekens, J. A., Portengen, H., van Putten, W. L. J., Peters, H. A., Krijnen, HLJM, Alexieva-Figusch, J. & Klijn, J. G. M. (1989). Prognostic value of estrogen and progesterone receptors measured by enzyme immunoassays in human breast tumor cytosols. Cancer Res 49: 5823–5228.
Foekens, J. A., Schmitt, M., van Putten, W. L. J., Peters, H. A., Bontenbal, M., Jänicke, F. & Klijn, J. G. M. (1992). Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients. Cancer Res 52: 6101–6105.
Foekens, J. A., Schmitt, M., van Putten, W. L. J., Peters, H. A., Kramer, M. D., Jänicke, F. & Klijn, J. G. M. (1994). Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. J Clin Oncol 12: 6148–1658.
Grebenschikov, N., Geurts-Moespot, A., De Witte, H., Heuvel, J., Leake, R., Sweep, F. & Benraad, T. (1997). 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 12: 6–14.
Grøndahl-Hansen, J., Christensen, I. J., Rosenquist, C., Brünner, N., Mouridsen, H. T., Danø, K. & Blichert-Toft, M. (1993). 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 53: 2513–2521.
Jänicke, F., Schmitt, M., Ulm, K., Gössner, W. & Graeff, H. (1989). Urokinase-type plasminogen activator antigen and early relapse in breast cancer. Lancet 8670: 1049
Jänicke, F., Schmitt, M., Hafter, R., Hollrieder, A., Babic, R., Ulm, K., Gössner, W. & Graeff, H. (1990). Urokinase-type plasminogen activator (u-PA) antigen is a predictor of early relapse in breast cancer. Fibrinolysis 4: 69–78.
Jänicke, F., Schmitt, M. & Graeff, H. (1991). Clinical relevance of the urokinase-type and tissue-type plasminogen activators and of their type-1 inhibitor in breast cancer. Semin Thromb Hemostas 17: 303–312.
Jänicke, F., Schmitt, M., Pache, L., Ulm, K., Harbeck, N., Höfler, H. & Graeff, H. (1993). Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 24: 195–208.
Jänicke, F., Pache, L., Schmitt, M., Ulm, K., Thomssen, C., Prechtl, A. & Graeff, H. (1994a). 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 54: 2527–2530.
Jänicke, F., Thomssen, C., Pache, L., Schmitt, M. & Graeff, H. (1994b). Urokinase (uPA) and PAI-1 as selection criteria for adjuvant chemotherapy in axillary node-negative breast cancer patients. In Prospects in Diagnosis and Treatment of Breast Cancer, Schmitt M, Graeff H, Kindermann G (eds), pp. 207–218, Elsevier Publishers: Amsterdam
Kaplan, E. L. & Meier, P. (1958). Nonparametric estimation from incomplete observation. J Am Stat Assoc 53: 457–481.
Liotta, L. A., Thorgeirsson, U. P. & Garbisa, S. (1982). Role of collagenases in tumor cell invasion, tissue degradation, and cancer. Cancer Metastasis Rev 1: 277–297.
Mignatti, P. & Rifkin, D. B. (1993). Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 73: 161–195.
Schmitt, M., Harbeck, N., Thomssen, C., Wilhelm, O., Magdolen, V., Reuning, U., Ulm, K., Höfler, H., Jänicke, F. & Graeff, H. (1997). Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy. Thromb Haemost 78: 285–296.
Spyratos, F., Martin, P-M, Hacène, K., Romain, S., Andrieu, C., Ferrero-Poüs, M., Deytieux, S., Le Doussal, V., Tubiana-Hulin, M. & Brunet, M. (1992). Multiparametric prognostic evaluation of biological factors in primary breast cancer. J Natl Cancer Inst 84: 1266–1272.
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de Witte, J., Sweep, C., Klijn, J. et al. Prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) in cytosols and pellet extracts derived from 892 breast cancer patients. Br J Cancer 79, 1190–1198 (1999). https://doi.org/10.1038/sj.bjc.6690191
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DOI: https://doi.org/10.1038/sj.bjc.6690191
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