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Thromb Haemost 2004; 91(02): 403-411
DOI: 10.1160/TH03-06-0351
Cellular Proteolysis and Oncology
Schattauer GmbH

Metabolism of tumour-derived urokinase receptor and receptor fragments in cancer patients and xenografted mice

Cornelis F.M. Sier   #   *
1   Department of Molecular Biology and Functional Genomics and FIRC Institute of Molecular Oncology
,
Ines Nicoletti   *
3   Department of Oncology, Mario Negri Institute for Pharmacological Research, Bergamo, Italy
,
Maria Lisa Santovito
1   Department of Molecular Biology and Functional Genomics and FIRC Institute of Molecular Oncology
,
Thomas Frandsen
5   H:S Hvidovre Hospital, Pediatric Department, Hvidovre, Denmark
,
Giovanni Aletti
2   Department of Gynaecology and Obstetrics, San Raffaele Scientific Institute and Hospital, Milan, Italy
,
Augusto Ferrari
2   Department of Gynaecology and Obstetrics, San Raffaele Scientific Institute and Hospital, Milan, Italy
,
Andrea Lissoni
4   Department of Gynaecology and Obstetrics, S. Gerardo Hospital, Monza, Italy
,
Raffaella Giavazzi
3   Department of Oncology, Mario Negri Institute for Pharmacological Research, Bergamo, Italy
,
Francesco Blasi
1   Department of Molecular Biology and Functional Genomics and FIRC Institute of Molecular Oncology
,
Nicolai Sidenius
1   Department of Molecular Biology and Functional Genomics and FIRC Institute of Molecular Oncology
› Author AffiliationsFinancial support: This work was carried out under the auspices of the Centro di Eccellenza di Fisiopatologia del Differenziamento Cellulare (MIUR).The work was supported by the Italian Association for Cancer Research (AIRC), FIRB (grant numbers RBNE 01 JFFA001 and RBAU 01CHJJ001) and by the European Union (Contract No. QLG1-CT2000-01131). In addition the generous contribution of the Nerina and Mario Mattioli Foundation is gratefully acknowledged.
Further Information

Publication History

Received 10 June 2003

Accepted after revision 22 October 2003

Publication Date:
01 December 2017 (online)

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Summary

The urokinase-type plasminogen activator receptor (uPAR) is involved in cell migration and tissue remodelling, as a receptor for pro-uPA, as a cell adhesion component, and in a soluble form as a chemoattractant. We have analyzed the presence and the molecular forms of uPAR and uPAR-fragments in urine of ovarian cancer patients in comparison with tumour tissue, ascites, and serum. Carcinoma tissue contained high levels of uPAR, but more abundantly the D2D3-fragment. Ascitic fluid contained similar ratio’s of suPAR fragments as corresponding tumour tissue, but serum only contained intact suPAR. Interestingly, urine contained predominantly the uPAR-fragments D1 and D2D3, and the pattern of these fragments was different in cancer patients as compared to healthy individuals. To confirm the hypothesis that circulating and urinary suPAR and suPAR-fragments originate from the tumour tissue, the presence of human suPAR (fragments) was analyzed in mice xenografted with human tumours. Indeed, high levels of urinary D1 fragment were found in mice carrying a tumour displaying cleaved uPAR on the cell surface, but little or no D1 was found in the urine from mice carrying a tumour with full-length uPAR. Mouse serum contained only intact suPAR. Our data demonstrate that the enhanced levels of suPAR fragments in the urine of cancer patients is likely to originate from uPAR expressed in the tumour tissue. Considering the biological activities that uPAR fragments display, the level and typing of uPAR fragments in urine might therefore be clinically more relevant than the plain serum uPAR content.

Keywords

uPAR - cleavage - fragments - cancer - urine

# Present address: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands


* These authors contributed equally to the study.


 

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