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Physiological and pathological changes of plasma urokinase-type plasminogen activator, plasminogen activator inhibitor-1, and urokinase-type plasminogen activator receptor levels in healthy females and breast cancer patients

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Abstract

The plasma urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and urokinase-type plasminogen activator receptor (uPAR) levels were measured in healthy volunteers and breast cancer patients. In pre-menopause healthy females, blood was sampled weekly during one menstruation cycle and menstruation phases (follicular, ovulatory, luteal) were determined by FSH/LH levels. uPA, PAI-1, and uPAR levels were at the nadir during ovulatory phase. uPA level was highest at follicular phase while PAI-1 level was highest at luteal phase. In comparison between pre- and post-menopause states, uPA and uPAR levels were higher in post-menopause state while PAI-1 level was higher in pre-menopause state. In breast cancer patients, uPA, PAI-1, and uPAR positive rates were low when we use the menopause-state-unmatched cut-off points. As we adjusted the cut-off points by menopause states, the PAI-1 positivity increased mainly in post-menopause cancer patients. These findings suggest that there is a minor but possible sequential change of these molecules during menstruation cycle which might blur the pathological positivity in pre-menopause cancer patients. The pathological elevation of PAI-1 was well detected in post-menopause cancer patients, but this elevation did not correlate with tumor burden such as number of metastatic sites or metastatic location. In conclusion, adjustment of physiological changes of uPA, PAI-1, and uPAR is required in determining pathological elevation of the plasma levels in cancer patients, especially in females.

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References

  1. Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991

    Article  PubMed  Google Scholar 

  2. Vassalli JD, Baccino D, Belin D: A cellular binding site for the Mr 55,000 form of the plasminogen activator, urokinase. J Cell Biol 100: 86–92, 1985.

    Article  PubMed  Google Scholar 

  3. Ellis V, Behrendt N, Dano K: Plasminogen activation by receptor-bound urokinase. A kinetic study with both cell-associated and isolated receptor. J Biol Chem 266: 12752–12758, 1991

    PubMed  Google Scholar 

  4. Andreasen PA, Georg B, Lund LR, Riccio A, Stacey SN: Plasminogen activator inhibitors: hormonally regulated serpines. Moll Cell Endocrinol 68: 1–19, 1990

    Article  Google Scholar 

  5. Cubelis MV, Wun TC, Blasi F: Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PAI-1. EMBO J 9: 1079–1085, 1990

    PubMed  Google Scholar 

  6. Olson D, Pollanen J, Hoyer-Hansen G: Internalization of the urokinase plasminogen activator inhibitor type-1 complex is mediated by the urokinase receptor. J Biol Chem 267: 9129–9133, 1991

    Google Scholar 

  7. Duffy MJ, Reilly D, O'Sullivan C, O'Higgins N, Femmelly JJ, Lijnen H: Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer. Cancer Res 50: 6827–6829, 1990

    PubMed  Google Scholar 

  8. Janicke F, Schmitt M, Hafter R, Hollrieder A, Babic R, Ulm K, Gossner W, Graeff H: Urokinase-type plasminogen activator (uPA) antigen is a predictor of early relapse in breast cancer. Fibrinolysis 4, 69–78, 1990

    Article  Google Scholar 

  9. Foekens JA, Schmitt M, van Putten WLJ, Peters HA, Bontenbal M, Janicke F, Klijn JGM: Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients. Cancer Res 52: 6101–6105, 1992

    PubMed  Google Scholar 

  10. Yamamoto M, Sawaya R, Mohanam S, Bindal AK, Bruner JM, Oka K, Rao VH, Tamonaga M, Nicholson GL, Rao JS: Expression and localization of urokinase-type plasminogen activator in human astrocytoma in vivo. Cancer Res 54: 3656–3661, 1994

    PubMed  Google Scholar 

  11. Pedersen H, Grondahl-Hansen J, Francis D, Osterlind K, Hansen HH, Dano K, Brunner N: Urokinase and plasminogen activator type-1 in pulmonary adenocarcinoma. Cancer Res 54: 120–123, 1994

    PubMed  Google Scholar 

  12. Ganesh S, Sier CFM, Griffioen G, Vloedgraven HJM, de Boer A, Welvaart K, van de Velde CJH, van Krieken JHJM, Verheijen JH, Lamers CBHW, Verspaget HW: Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer. Cancer Res 54: 4065–4071, 1994

    PubMed  Google Scholar 

  13. Grondahl-Hansen J, Christensen IJ, Rosenquist C, Brunner N, Mouridsen HT, Dano K, Blichert-Toft M: 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, 1993

    PubMed  Google Scholar 

  14. Fockens JA, Schmitt M, van Putten WLJ, Peters HA, Kramer MD, Janicke F, Klijn JGM: Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. J Clin Oncol 12: 1648–1658, 1994

    PubMed  Google Scholar 

  15. Janicke F, Schmitt M, Pache L, Ulm K, Harbeck N, Hofler H, Graeff H: 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, 1993

    Article  PubMed  Google Scholar 

  16. Bouchet C, Spyratos F, Martin PM: Prognostic value of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor PAI-1 and PAI-2 in breast carcinomas. Br J Cancer 69: 398–405, 1994

    PubMed  Google Scholar 

  17. Foekens J, Look MP, Peters HA, van Putten WLJ, Portengen H, Klijn JGM: Urokinase-type plasminogen activator and its inhibitor PAI-1: predictors of poor response to tamoxifen therapy in recurrent breast cancer. J Natl Cancer Inst 87: 751–756, 1995

    PubMed  Google Scholar 

  18. Buo L, Meling GI, Karlsrud TS, Johansen HT, Aasen AO: Antigen levels of urokinase plasminogen activator and its receptor at the tumor-host interface of colorecal adenocarcinomas are related to tumor aggressiveness. Hum Pathol 26: 1133–1138, 1995

    Article  PubMed  Google Scholar 

  19. Huber K, Kirchheimer JC, Sedlmayer A, Bell C, Ermler D, Binder BR: Clinical value of determination of urokinase-type plasminogen activator antigen in plasma for detection of colorectal cancer: comparison with circulating tumor-associated antigens CA 19-9 and carcinoembryonic antigen. Cancer Res 53: 1788–1793, 1993

    PubMed  Google Scholar 

  20. Casslen B, Bossmar T, Lecander I, Astedt B: Plasminogen activators and plasminogen activator inhibitors in blood and tumor fluids of patients with ovarian cancer. Eur J Cancer 30A: 1302–1309, 1994

    Article  PubMed  Google Scholar 

  21. Song KS, Lee A, Choi JR, Kwon OH: Diagnostic efficacy of plasma urokinase-type plasminogen activator and plasminogen activator inhibitor-2 in differentiation of hepatocellular carcinoma from cirrhosis. Throm Haemost 74: 864–867, 1995

    Google Scholar 

  22. Hildenbrand R, Dilger I, Horlin A, Stutte HJ: Urokinase plasminogen activator induces angiogenesis and tumor vessel invasion in breast cancer. Path Res Pract 1991: 403–409, 1995

    Google Scholar 

  23. Modlich U, Kaup FJ, Augustin HG: Cyclic angiogenesis and blood vessel regression in the ovary: blood vessel regression during luteolysis involves endothelial cell detachment and vessel occlusion. Lab Invest 74: 771–780, 1996

    PubMed  Google Scholar 

  24. Albers A, Thie M, Hohn HP, Denker HW: Differential expression and localization of integrins and CD44 in the membrane domains of human uterine epithelial cells during the menstrual cycle. Acta Anat 153: 12–19, 1995

    PubMed  Google Scholar 

  25. Hrushesky WJM, Bluming AZ, Gruber SA, Sothern RB: Menstrual influence on surgical cure of breast cancer. Lancet ii: 949–952, 1989

    Article  Google Scholar 

  26. Oliver DJ, Ingram DM: Timing of surgery during the menstruation cycle for breast cancer: possible role of growth factors. Eur J Cancer 31A: 325–328, 1995

    Article  PubMed  Google Scholar 

  27. Nguyen M, Watanabe H, Budson BE, Richie JP, Hayes DF, Folkman J: Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancer. J Natl Cancer Inst 86: 356–361, 1994

    PubMed  Google Scholar 

  28. Lin RY, Argenta PA, Sullivan KM, Adzick NS: Diagnostic and prognostic role of basic fibroblast growth factor in Wilms' tumor patients. Clin Cancer Res 1: 327–331, 1995

    PubMed  Google Scholar 

  29. Kondo S, Asano M, Matsuo K, Ohmori I, Suzuki H: Vascular endothelial growth factor/vascular permeability factor is detectable in the sera of tumor-bearing mice and cancer patients. Biochem Biophys Acta 1221: 211–214, 1994

    Article  PubMed  Google Scholar 

  30. Jensen PH, Christensen EI, Ebbesen P, Gliemann J, Andreasen PA: Lysosomal degradation of receptor-bound urokinase-type plasminogen activator is enhanced by its inhibitors in human trophoblastic choriocarcinoma cells. Cell Reg 1: 1043–1056, 1990

    Google Scholar 

  31. Grunaudo V, Hauert J, Kruithof EKO: Diurnal variation of the fibrinolytic system. Thromb Haemostasis 59: 495–499, 1988

    Google Scholar 

  32. Koelbl H, Kirchheimer JK, Tata G, Christ G, Binder BR: Increased plasma levels of urokinase-type plasminogen activator with endometrial and cervical cancer. Obstet Gynecol 72: 252–256, 1988

    PubMed  Google Scholar 

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Chung, H.C., Rha, S.Y., Park, J.O. et al. Physiological and pathological changes of plasma urokinase-type plasminogen activator, plasminogen activator inhibitor-1, and urokinase-type plasminogen activator receptor levels in healthy females and breast cancer patients. Breast Cancer Res Treat 49, 41–50 (1998). https://doi.org/10.1023/A:1005997421733

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