Abstract
Patients with an elevated level of urokinase plasminogen activator (uPA) in breast cancer tissue have an adverse prognosis. This study evaluated the prognostic relevance of uPA detection in disseminated tumour cells in bone marrow. Bone marrow was sampled intraoperatively from both iliac crests in 280 patients with primary breast cancer. Interphase cells were enhanced and stained immunocytologically with two antibodies: 2E11, which detects TAG 12--a tumour-associated glycoprotein typically expressed by almost all breast cancer cells--and the anti-uPA antibody HD-UK9. Thirty-five of the 2E11-positive women (n = 132, 47%) developed metastatic disease (median follow-up time 44 months). Of these, most were uPA positive (n = 23, 65%) and only 12 were uPA negative. Patients with uPA-positive cells in bone marrow (n = 98, 35%) had a significantly shorter metastasis-free interval (36 months) than women who were uPA negative (44.5 months). The worst prognosis was seen in patients positive for both markers (29.5 months), followed by those who were uPA negative and 2E11 positive (37 months). The detection of uPA on disseminated tumour cells characterizes a subgroup of patients with an even worse prognosis, who should undergo more aggressive adjuvant systemic therapy. For the first time, it was possible to evaluate an important qualitative parameter involved in the process of breast cancer metastases.
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- Bianchi E., Cohen R. L., Thor A. T., Todd R. F., 3rd, Mizukami I. F., Lawrence D. A., Ljung B. M., Shuman M. A., Smith H. S. The urokinase receptor is expressed in invasive breast cancer but not in normal breast tissue. Cancer Res. 1994 Feb 15;54(4):861–866. [PubMed] [Google Scholar]
- Cantero D., Friess H., Deflorin J., Zimmermann A., Bründler M. A., Riesle E., Korc M., Büchler M. W. Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma. Br J Cancer. 1997;75(3):388–395. doi: 10.1038/bjc.1997.63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Christensen L., Wiborg Simonsen A. C., Heegaard C. W., Moestrup S. K., Andersen J. A., Andreasen P. A. Immunohistochemical localization of urokinase-type plasminogen activator, type-1 plasminogen-activator inhibitor, urokinase receptor and alpha(2)-macroglobulin receptor in human breast carcinomas. Int J Cancer. 1996 May 16;66(4):441–452. doi: 10.1002/(SICI)1097-0215(19960516)66:4<441::AID-IJC6>3.0.CO;2-W. [DOI] [PubMed] [Google Scholar]
- Costantini V., Sidoni A., Deveglia R., Cazzato O. A., Bellezza G., Ferri I., Bucciarelli E., Nenci G. G. Combined overexpression of urokinase, urokinase receptor, and plasminogen activator inhibitor-1 is associated with breast cancer progression: an immunohistochemical comparison of normal, benign, and malignant breast tissues. Cancer. 1996 Mar 15;77(6):1079–1088. doi: 10.1002/(sici)1097-0142(19960315)77:6<1079::aid-cncr12>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
- Cote R. J., Rosen P. P., Lesser M. L., Old L. J., Osborne M. P. Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases. J Clin Oncol. 1991 Oct;9(10):1749–1756. doi: 10.1200/JCO.1991.9.10.1749. [DOI] [PubMed] [Google Scholar]
- Diel I. J., Kaufmann M., Costa S. D., Bastert G. Monoclonal antibodies to detect breast cancer cells in bone marrow. Important Adv Oncol. 1994:143–164. [PubMed] [Google Scholar]
- Diel I. J., Kaufmann M., Costa S. D., Holle R., von Minckwitz G., Solomayer E. F., Kaul S., Bastert G. Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. J Natl Cancer Inst. 1996 Nov 20;88(22):1652–1658. doi: 10.1093/jnci/88.22.1652. [DOI] [PubMed] [Google Scholar]
- Diel I. J., Kaufmann M., Goerner R., Costa S. D., Kaul S., Bastert G. Detection of tumor cells in bone marrow of patients with primary breast cancer: a prognostic factor for distant metastasis. J Clin Oncol. 1992 Oct;10(10):1534–1539. doi: 10.1200/JCO.1992.10.10.1534. [DOI] [PubMed] [Google Scholar]
- Duffy M. J., Reilly D., McDermott E., O'Higgins N., Fennelly J. J., Andreasen P. A. Urokinase plasminogen activator as a prognostic marker in different subgroups of patients with breast cancer. Cancer. 1994 Oct 15;74(8):2276–2280. doi: 10.1002/1097-0142(19941015)74:8<2276::aid-cncr2820740811>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
- Duffy M. J., Reilly D., O'Sullivan C., O'Higgins N., Fennelly J. J., Andreasen P. Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer. Cancer Res. 1990 Nov 1;50(21):6827–6829. [PubMed] [Google Scholar]
- 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]
- Foekens J. A., Look M. P., Peters H. A., van Putten W. L., Portengen H., Klijn J. G. 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 May 17;87(10):751–756. doi: 10.1093/jnci/87.10.751. [DOI] [PubMed] [Google Scholar]
- Foekens J. A., Schmitt M., van Putten W. L., Peters H. A., Bontenbal M., Jänicke F., Klijn J. G. Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients. Cancer Res. 1992 Nov 1;52(21):6101–6105. [PubMed] [Google Scholar]
- Foekens J. A., Schmitt M., van Putten W. L., Peters H. A., Kramer M. D., Jänicke F., Klijn J. G. Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. J Clin Oncol. 1994 Aug;12(8):1648–1658. doi: 10.1200/JCO.1994.12.8.1648. [DOI] [PubMed] [Google Scholar]
- Foucré D., Bouchet C., Hacène K., Pourreau-Schneider N., Gentile A., Martin P. M., Desplaces A., Oglobine J. Relationship between cathepsin D, urokinase, and plasminogen activator inhibitors in malignant vs benign breast tumours. Br J Cancer. 1991 Nov;64(5):926–932. doi: 10.1038/bjc.1991.428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ganesh S., Sier C. F., Heerding M. M., Griffioen G., Lamers C. B., Verspaget H. W. Urokinase receptor and colorectal cancer survival. Lancet. 1994 Aug 6;344(8919):401–402. doi: 10.1016/s0140-6736(94)91427-3. [DOI] [PubMed] [Google Scholar]
- Grøndahl-Hansen J., Christensen I. J., Rosenquist C., Brünner N., Mouridsen H. T., Danø 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. 1993 Jun 1;53(11):2513–2521. [PubMed] [Google Scholar]
- 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]
- Heiss M. M., Babic R., Allgayer H., Gruetzner K. U., Jauch K. W., Loehrs U., Schildberg F. W. Tumor-associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system. J Clin Oncol. 1995 Aug;13(8):2084–2093. doi: 10.1200/JCO.1995.13.8.2084. [DOI] [PubMed] [Google Scholar]
- Henderson B. R., Tansey W. P., Phillips S. M., Ramshaw I. A., Kefford R. F. Transcriptional and posttranscriptional activation of urokinase plasminogen activator gene expression in metastatic tumor cells. Cancer Res. 1992 May 1;52(9):2489–2496. [PubMed] [Google Scholar]
- Jänicke F., Schmitt M., Pache L., Ulm K., Harbeck N., Höfler 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. 1993;24(3):195–208. doi: 10.1007/BF01833260. [DOI] [PubMed] [Google Scholar]
- Landys K. A new trephine for closed bone marrow biopsy. Acta Haematol. 1980;64(4):216–220. doi: 10.1159/000207254. [DOI] [PubMed] [Google Scholar]
- Mansi J. L., Berger U., Easton D., McDonnell T., Redding W. H., Gazet J. C., McKinna A., Powles T. J., Coombes R. C. Micrometastases in bone marrow in patients with primary breast cancer: evaluation as an early predictor of bone metastases. Br Med J (Clin Res Ed) 1987 Oct 31;295(6606):1093–1096. doi: 10.1136/bmj.295.6606.1093. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mayer M. Biochemical and biological aspects of the plasminogen activation system. Clin Biochem. 1990 Jun;23(3):197–211. doi: 10.1016/0009-9120(90)90601-p. [DOI] [PubMed] [Google Scholar]
- Needham G. K., Nicholson S., Angus B., Farndon J. R., Harris A. L. Relationship of membrane-bound tissue type and urokinase type plasminogen activators in human breast cancers to estrogen and epidermal growth factor receptors. Cancer Res. 1988 Nov 15;48(22):6603–6607. [PubMed] [Google Scholar]
- Nekarda H., Schmitt M., Ulm K., Wenninger A., Vogelsang H., Becker K., Roder J. D., Fink U., Siewert J. R. Prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in completely resected gastric cancer. Cancer Res. 1994 Jun 1;54(11):2900–2907. [PubMed] [Google Scholar]
- Orr F. W., Kostenuik P., Sanchez-Sweatman O. H., Singh G. Mechanisms involved in the metastasis of cancer to bone. Breast Cancer Res Treat. 1993;25(2):151–163. doi: 10.1007/BF00662140. [DOI] [PubMed] [Google Scholar]
- Osborne M. P., Wong G. Y., Asina S., Old L. J., Cote R. J., Rosen P. P. Sensitivity of immunocytochemical detection of breast cancer cells in human bone marrow. Cancer Res. 1991 May 15;51(10):2706–2709. [PubMed] [Google Scholar]
- Ossowski L., Russo-Payne H., Wilson E. L. Inhibition of urokinase-type plasminogen activator by antibodies: the effect on dissemination of a human tumor in the nude mouse. Cancer Res. 1991 Jan 1;51(1):274–281. [PubMed] [Google Scholar]
- Pantel K., Schlimok G., Braun S., Kutter D., Lindemann F., Schaller G., Funke I., Izbicki J. R., Riethmüller G. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst. 1993 Sep 1;85(17):1419–1424. doi: 10.1093/jnci/85.17.1419. [DOI] [PubMed] [Google Scholar]
- Pedersen H., Brünner N., Francis D., Osterlind K., Rønne E., Hansen H. H., Danø K., Grøndahl-Hansen J. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res. 1994 Sep 1;54(17):4671–4675. [PubMed] [Google Scholar]
- Pyke C., Graem N., Ralfkiaer E., Rønne E., Høyer-Hansen G., Brünner N., Danø K. Receptor for urokinase is present in tumor-associated macrophages in ductal breast carcinoma. Cancer Res. 1993 Apr 15;53(8):1911–1915. [PubMed] [Google Scholar]
- Riesenberg R., Oberneder R., Kriegmair M., Epp M., Bitzer U., Hofstetter A., Braun S., Riethmüller G., Pantel K. Immunocytochemical double staining of cytokeratin and prostate specific antigen in individual prostatic tumour cells. Histochemistry. 1993 Jan;99(1):61–66. doi: 10.1007/BF00268022. [DOI] [PubMed] [Google Scholar]
- Rosen P. R., Groshen S., Saigo P. E., Kinne D. W., Hellman S. A long-term follow-up study of survival in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma. J Clin Oncol. 1989 Mar;7(3):355–366. doi: 10.1200/JCO.1989.7.3.355. [DOI] [PubMed] [Google Scholar]
- Schlimok G., Funke I., Holzmann B., Göttlinger G., Schmidt G., Häuser H., Swierkot S., Warnecke H. H., Schneider B., Koprowski H. Micrometastatic cancer cells in bone marrow: in vitro detection with anti-cytokeratin and in vivo labeling with anti-17-1A monoclonal antibodies. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8672–8676. doi: 10.1073/pnas.84.23.8672. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schmitt M., Jänicke F., Graeff H. Tumour-associated fibrinolysis: the prognostic relevance of plasminogen activators uPA and tPA in human breast cancer. Blood Coagul Fibrinolysis. 1990 Dec;1(6):695–702. [PubMed] [Google Scholar]
- Schmitt M., Jänicke F., Moniwa N., Chucholowski N., Pache L., Graeff H. Tumor-associated urokinase-type plasminogen activator: biological and clinical significance. Biol Chem Hoppe Seyler. 1992 Jul;373(7):611–622. doi: 10.1515/bchm3.1992.373.2.611. [DOI] [PubMed] [Google Scholar]
- Seifert J., Machková Z. Biosynthesis of pyrimidine nucleotides and level of cytochrome P-450 in rat liver and kidney after clofibrate administration (an in vivo study). J Cancer Res Clin Oncol. 1988;114(1):59–63. doi: 10.1007/BF00390486. [DOI] [PubMed] [Google Scholar]
- Untch M., Harbeck N., Eiermann W. Micrometastases in bone marrow in patients with breast cancer. Br Med J (Clin Res Ed) 1988 Jan 23;296(6617):290–290. doi: 10.1136/bmj.296.6617.290. [DOI] [PMC free article] [PubMed] [Google Scholar]