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

Cornelis F.M. Sier; Ines Nicoletti; Maria Lisa Santovito; Thomas Frandsen; Giovanni Aletti; Augusto Ferrari; Andrea Lissoni; Raffaella Giavazzi; Francesco Blasi; Nicolai Sidenius

doi:10.1160/TH03-06-0351

Thrombosis and Haemostasis, Table of Contents

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

Authors

Cornelis F.M. Sier^#^*

¹Department of Molecular Biology and Functional Genomics and FIRC Institute of Molecular Oncology
Ines Nicoletti^*

³Department of Oncology, Mario Negri Institute for Pharmacological Research, Bergamo, Italy
Maria Lisa Santovito

¹Department of Molecular Biology and Functional Genomics and FIRC Institute of Molecular Oncology
Thomas Frandsen

⁵H:S Hvidovre Hospital, Pediatric Department, Hvidovre, Denmark
Giovanni Aletti

²Department of Gynaecology and Obstetrics, San Raffaele Scientific Institute and Hospital, Milan, Italy
Augusto Ferrari

²Department of Gynaecology and Obstetrics, San Raffaele Scientific Institute and Hospital, Milan, Italy
Andrea Lissoni

⁴Department of Gynaecology and Obstetrics, S. Gerardo Hospital, Monza, Italy
Raffaella Giavazzi

³Department of Oncology, Mario Negri Institute for Pharmacological Research, Bergamo, Italy
Francesco Blasi

¹Department of Molecular Biology and Functional Genomics and FIRC Institute of Molecular Oncology
Nicolai Sidenius

¹Department of Molecular Biology and Functional Genomics and FIRC Institute of Molecular Oncology

Abstract

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

Full Text

References

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