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. 2001 Jul;85(1):85–92. doi: 10.1054/bjoc.2001.1867

Prognostic impact of urokinase-type plasminogen activator receptor (uPAR) in cytosols and pellet extracts derived from primary breast tumours

J H de Witte 1, J A Foekens 2, N Brünner 3, J J T M Heuvel 1, ThH van Tienoven 1, M P Look 2, J G M Klijn 2, A Geurts-Moespot 1, N Grebenchtchikov 1, ThJ Benraad 1, C G J Sweep 1
PMCID: PMC2363926  PMID: 11437407

Abstract

Using a previously developed enzyme-linked immunosorbent assay (ELISA), the levels of the receptor for urokinase-type plasminogen activator (uPAR) were determined in cytosols and corresponding membrane pellets derived from 878 primary breast tumours. The levels of uPAR in the pellet extracts were more than 3-fold higher than those measured in the cytosols (P< 0.001). Moreover, the uPAR levels in the two types of extracts were weakly, though significantly, correlated with each other (rS= 0.20, P< 0.001). In Cox univariate analysis, high cytosolic levels of uPAR were significantly associated with reduced overall survival (OS) and relapse-free survival (RFS). The levels of uPAR in pellet extracts appeared not to be related with patient survival. In multivariate analysis, elevated levels of uPAR measured in cytosols and pellet extracts were found to be independent predictors of poor OS, not RFS. The prediction of poor prognosis on the basis of high uPAR levels emphasizes its important role in plasmin-mediated degradation of extracellular matrix proteins during cancer invasion and metastasis. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Selected References

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  1. Andreasen P. A., Georg B., Lund L. R., Riccio A., Stacey S. N. Plasminogen activator inhibitors: hormonally regulated serpins. Mol Cell Endocrinol. 1990 Jan 2;68(1):1–19. doi: 10.1016/0303-7207(90)90164-4. [DOI] [PubMed] [Google Scholar]
  2. Andreasen P. A., Kjøller L., Christensen L., Duffy M. J. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer. 1997 Jul 3;72(1):1–22. doi: 10.1002/(sici)1097-0215(19970703)72:1<1::aid-ijc1>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  3. Behrendt N., Ronne E., Dano 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 Sep 13;271(37):22885–22894. doi: 10.1074/jbc.271.37.22885. [DOI] [PubMed] [Google Scholar]
  4. Behrendt N., Rønne E., Danø K. The structure and function of the urokinase receptor, a membrane protein governing plasminogen activation on the cell surface. Biol Chem Hoppe Seyler. 1995 May;376(5):269–279. [PubMed] [Google Scholar]
  5. Bouchet C., Hacène K., Martin P. M., Becette V., Tubiana-Hulin M., Lasry S., Oglobine J., Spyratos F. Dissemination risk index based on plasminogen activator system components in primary breast cancer. J Clin Oncol. 1999 Oct;17(10):3048–3057. doi: 10.1200/JCO.1999.17.10.3048. [DOI] [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  7. Chapman H. A. Plasminogen activators, integrins, and the coordinated regulation of cell adhesion and migration. Curr Opin Cell Biol. 1997 Oct;9(5):714–724. doi: 10.1016/s0955-0674(97)80126-3. [DOI] [PubMed] [Google Scholar]
  8. Danø K., Andreasen P. A., Grøndahl-Hansen J., Kristensen P., Nielsen L. S., Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139–266. doi: 10.1016/s0065-230x(08)60028-7. [DOI] [PubMed] [Google Scholar]
  9. Duffy M. J. Proteases as prognostic markers in cancer. Clin Cancer Res. 1996 Apr;2(4):613–618. [PubMed] [Google Scholar]
  10. Duffy M. J. The role of proteolytic enzymes in cancer invasion and metastasis. Clin Exp Metastasis. 1992 May;10(3):145–155. doi: 10.1007/BF00132746. [DOI] [PubMed] [Google Scholar]
  11. Duggan C., Maguire T., McDermott E., O'Higgins N., Fennelly J. J., Duffy M. J. Urokinase plasminogen activator and urokinase plasminogen activator receptor in breast cancer. Int J Cancer. 1995 May 29;61(5):597–600. doi: 10.1002/ijc.2910610502. [DOI] [PubMed] [Google Scholar]
  12. Ellis V., Behrendt N., Danø K. Plasminogen activation by receptor-bound urokinase. A kinetic study with both cell-associated and isolated receptor. J Biol Chem. 1991 Jul 5;266(19):12752–12758. [PubMed] [Google Scholar]
  13. Foekens J. A., Peters H. A., Look M. P., Portengen H., Schmitt M., Kramer M. D., Brünner N., Jänicke F., Meijer-van Gelder M. E., Henzen-Logmans S. C. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res. 2000 Feb 1;60(3):636–643. [PubMed] [Google Scholar]
  14. Foekens J. A., Portengen H., van Putten W. L., Peters H. A., Krijnen H. L., Alexieva-Figusch J., Klijn J. G. Prognostic value of estrogen and progesterone receptors measured by enzyme immunoassays in human breast tumor cytosols. Cancer Res. 1989 Nov 1;49(21):5823–5828. [PubMed] [Google Scholar]
  15. Grøndahl-Hansen J., Peters H. A., van Putten W. L., Look M. P., Pappot H., Rønne E., Dano K., Klijn J. G., Brünner N., Foekens J. A. Prognostic significance of the receptor for urokinase plasminogen activator in breast cancer. Clin Cancer Res. 1995 Oct;1(10):1079–1087. [PubMed] [Google Scholar]
  16. Kanse S. M., Kost C., Wilhelm O. G., Andreasen P. A., Preissner K. T. The urokinase receptor is a major vitronectin-binding protein on endothelial cells. Exp Cell Res. 1996 May 1;224(2):344–353. doi: 10.1006/excr.1996.0144. [DOI] [PubMed] [Google Scholar]
  17. Kristensen P., Eriksen J., Blasi F., Danø K. Two alternatively spliced mouse urokinase receptor mRNAs with different histological localization in the gastrointestinal tract. J Cell Biol. 1991 Dec;115(6):1763–1771. doi: 10.1083/jcb.115.6.1763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Liotta L. A., Thorgeirsson U. P., Garbisa S. Role of collagenases in tumor cell invasion. Cancer Metastasis Rev. 1982;1(4):277–288. doi: 10.1007/BF00124213. [DOI] [PubMed] [Google Scholar]
  19. Look M. P., Foekens J. A. Clinical relevance of the urokinase plasminogen activator system in breast cancer. APMIS. 1999 Jan;107(1):150–159. doi: 10.1111/j.1699-0463.1999.tb01538.x. [DOI] [PubMed] [Google Scholar]
  20. Mignatti P., Rifkin D. B. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev. 1993 Jan;73(1):161–195. doi: 10.1152/physrev.1993.73.1.161. [DOI] [PubMed] [Google Scholar]
  21. Pappot H., Høyer-Hansen G., Rønne E., Hansen H. H., Brünner N., Danø K., Grøndahl-Hansen J. Elevated plasma levels of urokinase plasminogen activator receptor in non-small cell lung cancer patients. Eur J Cancer. 1997 May;33(6):867–872. doi: 10.1016/s0959-8049(96)00523-0. [DOI] [PubMed] [Google Scholar]
  22. Ploug M., Eriksen J., Plesner T., Hansen N. E., Danø K. A soluble form of the glycolipid-anchored receptor for urokinase-type plasminogen activator is secreted from peripheral blood leukocytes from patients with paroxysmal nocturnal hemoglobinuria. Eur J Biochem. 1992 Sep 1;208(2):397–404. doi: 10.1111/j.1432-1033.1992.tb17200.x. [DOI] [PubMed] [Google Scholar]
  23. Ploug M., Rønne E., Behrendt N., Jensen A. L., Blasi F., Danø K. Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol. J Biol Chem. 1991 Jan 25;266(3):1926–1933. [PubMed] [Google Scholar]
  24. Pyke C., Eriksen J., Solberg H., Nielsen B. S., Kristensen P., Lund L. R., Danø K. An alternatively spliced variant of mRNA for the human receptor for urokinase plasminogen activator. FEBS Lett. 1993 Jul 12;326(1-3):69–74. doi: 10.1016/0014-5793(93)81763-p. [DOI] [PubMed] [Google Scholar]
  25. Rønne E., Behrendt N., Ploug M., Nielsen H. J., Wöllisch E., Weidle U., Danø K., Høyer-Hansen G. Quantitation of the receptor for urokinase plasminogen activator by enzyme-linked immunosorbent assay. J Immunol Methods. 1994 Jan 3;167(1-2):91–101. doi: 10.1016/0022-1759(94)90078-7. [DOI] [PubMed] [Google Scholar]
  26. Rønne E., Høyer-Hansen G., Brünner N., Pedersen H., Rank F., Osborne C. K., Clark G. M., Danø K., Grøndahl-Hansen J. Urokinase receptor in breast cancer tissue extracts. Enzyme-linked immunosorbent assay with a combination of mono- and polyclonal antibodies. Breast Cancer Res Treat. 1995 Mar;33(3):199–207. doi: 10.1007/BF00665944. [DOI] [PubMed] [Google Scholar]
  27. Schmitt M., Harbeck N., Thomssen C., Wilhelm O., Magdolen V., Reuning U., Ulm K., Höfler H., Jänicke F., Graeff H. Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy. Thromb Haemost. 1997 Jul;78(1):285–296. [PubMed] [Google Scholar]
  28. Sier C. F., Stephens R., Bizik J., Mariani A., Bassan M., Pedersen N., Frigerio L., Ferrari A., Danø K., Brünner N. The level of urokinase-type plasminogen activator receptor is increased in serum of ovarian cancer patients. Cancer Res. 1998 May 1;58(9):1843–1849. [PubMed] [Google Scholar]
  29. Stephens R. W., Pedersen A. N., Nielsen H. J., Hamers M. J., Høyer-Hansen G., Rønne E., Dybkjaer E., Danø K., Brünner N. ELISA determination of soluble urokinase receptor in blood from healthy donors and cancer patients. Clin Chem. 1997 Oct;43(10):1868–1876. [PubMed] [Google Scholar]
  30. Wei Y., Lukashev M., Simon D. I., Bodary S. C., Rosenberg S., Doyle M. V., Chapman H. A. Regulation of integrin function by the urokinase receptor. Science. 1996 Sep 13;273(5281):1551–1555. doi: 10.1126/science.273.5281.1551. [DOI] [PubMed] [Google Scholar]
  31. Wei Y., Waltz D. A., Rao N., Drummond R. J., Rosenberg S., Chapman H. A. Identification of the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem. 1994 Dec 23;269(51):32380–32388. [PubMed] [Google Scholar]
  32. de Witte H., Pappot H., Brünner N., Grøndahl-Hansen J., Hoyer-Hansen G., Behrendt N., Guldhammer-Skov B., Sweep F., Benraad T., Danø K. ELISA for complexes between urokinase-type plasminogen activator and its receptor in lung cancer tissue extracts. Int J Cancer. 1997 Jul 29;72(3):416–423. doi: 10.1002/(sici)1097-0215(19970729)72:3<416::aid-ijc8>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  33. de Witte J. H., Sweep C. G., Klijn J. G., Grebenschikov N., Peters H. A., Look M. P., van Tienoven T. H., Heuvel J. J., Bolt-De Vries J., Benraad T. J. Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer. Br J Cancer. 1999 Apr;80(1-2):286–294. doi: 10.1038/sj.bjc.6690353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. de Witte J. H., Sweep C. G., Klijn J. G., Grebenschikov N., Peters H. A., Look M. P., van Tienoven T. H., Heuvel J. J., Bolt-De Vries J., Benraad T. J. Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer. Br J Cancer. 1999 Apr;80(1-2):286–294. doi: 10.1038/sj.bjc.6690353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. de Witte J. H., Sweep C. G., Klijn J. G., Grebenschikov N., Peters H. A., Look M. P., van Tienoven T. H., Heuvel J. J., van Putten W. L., Benraad T. J. 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. 1999 Mar;79(7-8):1190–1198. doi: 10.1038/sj.bjc.6690191. [DOI] [PMC free article] [PubMed] [Google Scholar]

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