Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Individual development and uPA–receptor expression of disseminated tumour cells in bone marrow: A reference to early systemic disease in solid cancer

Nature Medicine volume 1, pages 1035–1039 (1995)Cite this article

Abstract

It is unclear whether disseminated tumour cells detected in bone marrow in early stages of solid cancers indicate a subclinical systemic disease component determining the patient's fate or simply represent mainly irrelevant shed cells. Moreover, characteristics differentiating high and low metastatic potential of disseminated tumour cells are not defined. We performed repeated serial bone marrow biopsies during follow–up in operated gastric cancer patients. Most patients with later tumour relapse revealed either an increase or a constantly high number of tumour cells. In contrast, in patients without recurrence, either clearance of tumour cells or negative or low cell counts were seen. Urokinase plasminogen activator (uPA)–receptor expression on disseminated tumour cells was significantly correlated with increasing tumour cell counts and clinical prognosis. These results demonstrate a systemic component in early solid cancer, indicated by early systemically disseminated tumour cells, which may predict individual disease development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Brisco, M.J. et al. Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction. Lancet 343, 196–199 (1994).

    Article  CAS  Google Scholar 

  2. Yokota, S. et al. Use of polymerase chain reactions to monitor minimal residual disease in acute lymphoblastic leukemia patients. Blood 77, 331–339 (1991).

    CAS  PubMed  Google Scholar 

  3. Riethmueller, G. & Johnson, J. Monoclonal antibodies in the detection and therapy of micrometastatic epithelial cancer. Curr. Opin. Immun. 4, 647–655 (1992).

    Article  Google Scholar 

  4. Osborne, M.P. & Rosen, P.P. Detection and management of bone marrow micrometastases in breast cancer. Oncology 8, 25–31 (1994).

    CAS  PubMed  Google Scholar 

  5. Moss, T.J. et al. Prognostic value of immunocytologic detection of bone marrow metastases in neuroblastoma. NewEngl. J. Med. 324, 219–226 (1991).

    Article  CAS  Google Scholar 

  6. Lindemann, F., Schlimok, G., Dirschedl, P., Witte, J. & Riethmueller, G. Prognostic significance of micrometastatic tumor cells in bone marrow of colorectal cancer patients. Lancet 340, 685–689 (1992).

    Article  CAS  Google Scholar 

  7. Schlimok, G. et al. Micrometastatic cancer cells in bone marrow: In vitro detection with anti-cytokeratin and in vivo labeling with anti-17-lA monoclonal antibodies. Proc. natn. Acad. Set. U.S.A. 84, 8672–8676 (1987).

    Article  CAS  Google Scholar 

  8. Ghosh, A.K. et al. Detection of metastatic tumour cells in routine bone marrow smears by immunoalkaline phosphatase labelling with monoclonal antibodies. Brit J. Haematol. 61, 21–30 (1985).

    Article  CAS  Google Scholar 

  9. Heiss, M.M. et al. Detection of cytokeratin-positive cells in bone marrow used as tumor marker in gastric cancer patients. in Tumor Associated Antigens, Oncogenes, Receptors, Cytokines in Tumor Diagnosis and Therapy at the Beginning of the Nineties, Cancer of the Breast — State and Trends in Diagnosis and Therapy (ed. Klapdor, R.) 471–473 (Zuckschwerdt, Munich, New York, 1992).

    Google Scholar 

  10. Pantel, K. et al. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J. natn. Cancer Inst. 85, 1419–1423 (1993).

    Article  CAS  Google Scholar 

  11. Berger, U. et al. The relationship between micrometastasis in the bone marrow, histopathologic features of the primary tumor in breast cancer and prognosis. Am. J. clin. Pathol. 90, 1–6 (1988).

    Article  CAS  Google Scholar 

  12. 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. 9, 1749–1756 (1991).

    Article  CAS  Google Scholar 

  13. Riesenberg, R. et al. Immunocytochemical double staining of cytokeratin and prostate specific antigen in individual prostatic tumour cells. Histochemistry 99, 61–66 (1993).

    Article  CAS  Google Scholar 

  14. Jauch, K.W., Gruetzner, U., Heiss, M.M., Funke, I. & Schildberg, F.W. Prognostic significance of early disseminated tumor cells in bone marrow of patients with gastric cancer, in First Intl. Gastric Cancer Congr., Kyoto, Japan Mar. 29–Apr. 1, 1995 (eds Nishi, M. et al.) 1021–1025 (Monduzzi Edi, Bologna, 1995).

  15. Mansi, J.L. et al The fate of bone marrow micrometastases in patients with primary breast cancer. J. clin. Oncol. 7, 445–449 (1989).

    Article  CAS  Google Scholar 

  16. Fidler, I. & Kripke, M.L. Metastasis results from pre-existing variant cells within a malignant tumor. Science 197, 893–895 (1977).

    Article  CAS  Google Scholar 

  17. Dvorak, H.F., Wounds that do not heal. New Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  Google Scholar 

  18. Duffy, M.J. The role of proteolytic enzymes in cancer invasion and metastasis. Clin. exp. Metastasis 10, 145–155 (1992).

    Article  CAS  Google Scholar 

  19. Ossowski, L., Clunie, G., Masucci, M.T. & Blasi, F. In vivo paracrine interaction between urokinase and its receptor: Effect on tumor cell invasion. J. Cell Biol. 115, 1107–1112 (1991).

    Article  CAS  Google Scholar 

  20. Blasi, F. Urokinase and urokinase receptor: A paracrine/autocrine system regulation cell migration and invasiveness. BioEssays 15, 105–111 (1993).

    Article  CAS  Google Scholar 

  21. Heiss, M.M. et al. Tumor-associated proteolysis and prognosis: New functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system. J. clin. Oncol. 13, 2084–2093 (1995).

    Article  CAS  Google Scholar 

  22. Nekarda, H. et al. Prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in completely resected gastric cancer. Cancer Res. 54, 2900–2907 (1994).

    CAS  PubMed  Google Scholar 

  23. Duffy, M.J. et al. Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer. Cancer Res. 50, 6827–6829 (1990).

    CAS  PubMed  Google Scholar 

  24. Moll, R., Franke, W.W., Schiller, D.L., Geiger, B. & Krepler, R. The catalogue of human cytokeratins: Pattern of expression in normal epithelia, tumors and cultured cells. Cell 31, 11–24 (1982).

    Article  CAS  Google Scholar 

  25. Breimann, L., Friedmann, J.H., Ohlsen, R.A. & Sone, C.J. Classification and Regression Trees (Waelswoth, Belmont, California, 1984).

    Google Scholar 

  26. Fazioli, F. & Blasi, F. Urokinase-type plasminogen activator and its receptor: New targets for anti-metastatic therapy. Trends Pharmac. Sci. 15, 25–29 (1994).

    Article  CAS  Google Scholar 

  27. Paget, S. Distribution of secondary growths in cancer of the breast. Lancet 1, 571 (1889).

    Article  Google Scholar 

  28. Wong, K.F., Chan, J.K. & Ma, S.K. Solid tumor with initial presentation in the bone marrow: A clinicopathologic study of 25 adult cases. Hematol.-Oncol. 11, 35–42 (1993).

    Article  CAS  Google Scholar 

  29. Frost, P., Raber, M.N. & Abbruzzese, J.L. Unknown primary tumors as a unique clinical and biological entity: A hypothesis. Cancer Bull. 41, 139–141 (1989).

    Google Scholar 

  30. Cordell, J.L. et al. Immunoenzymatic labelling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal antialkaline phosphatase (APAAP complexes). J. Histochem. Cytochem. 32, 219–229 (1984).

    Article  CAS  Google Scholar 

  31. Dixon, W.J. et al. BMDP Statistical Software (Univ. California Press, Los Angeles, 1985).

  32. Kaplan, E.L. & Meier, P. Nonparametric estimation from incomplete observation. J. Am. stat. Assoc. 53, 457–481 (1958).

    Article  Google Scholar 

  33. Cox, D.R. Regression models and life tables. J. R. stat Soc. (B) 34, 187–220 (1972).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, Klinikum Grosshadern, Ludwig Maximilians University of Munich, Marchionistrasse 15, 81377, Munich, Germany

    Markus Maria Heiss, Heike Allgayer, Klaus Uwe Gruetzner, Ilona Funke, Karl-Walter Jauch & Friedrich Wilhelm Schildberg

  2. Department of Pathology, Ludwig Maximilians University of Munich, 81377, Munich, Germany

    Rudolf Babic

Authors
  1. Markus Maria Heiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Heike Allgayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Klaus Uwe Gruetzner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ilona Funke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rudolf Babic
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karl-Walter Jauch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Friedrich Wilhelm Schildberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heiss, M., Allgayer, H., Gruetzner, K. et al. Individual development and uPA–receptor expression of disseminated tumour cells in bone marrow: A reference to early systemic disease in solid cancer. Nat Med 1, 1035–1039 (1995). https://doi.org/10.1038/nm1095-1035

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1095-1035

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing