Indication of a role of plasminogen activator inhibitor type 1 in protecting murine fibrosarcoma cells against apoptosis

Maria Unni Rømer; Anne Kirkebjerg Due; Jørgen Knud Larsen; Kenneth Francis Hofland; Ib Jarle Christensen; Peter Buhl-Jensen; Kasper Almholt; Ole Lerberg Nielsen; Nils Brünner; Ulrik Lademann

doi:10.1160/TH05-01-0011

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(04): 859-866
DOI: 10.1160/TH05-01-0011

Cellular Proteolysis and Oncology

Schattauer GmbH

Indication of a role of plasminogen activator inhibitor type 1 in protecting murine fibrosarcoma cells against apoptosis

Maria Unni Rømer

¹Institute of Veterinary Pathobiology, The Royal Veterinary and Agricultural University, Frederiksberg C, Denmark

²Department of Oncology, H:S Rigshospitalet, Copenhagen Ø., Denmark

,

Anne Kirkebjerg Due

¹Institute of Veterinary Pathobiology, The Royal Veterinary and Agricultural University, Frederiksberg C, Denmark

,

Jørgen Knud Larsen^*

¹Institute of Veterinary Pathobiology, The Royal Veterinary and Agricultural University, Frederiksberg C, Denmark

,

Kenneth Francis Hofland

²Department of Oncology, H:S Rigshospitalet, Copenhagen Ø., Denmark

,

Ib Jarle Christensen

³Department of Surgical Gastroenterology, H:S Hvidovre Hospital, Hvidovre, Denmark

,

Peter Buhl-Jensen

²Department of Oncology, H:S Rigshospitalet, Copenhagen Ø., Denmark

,

Kasper Almholt^*

¹Institute of Veterinary Pathobiology, The Royal Veterinary and Agricultural University, Frederiksberg C, Denmark

,

Ole Lerberg Nielsen

¹Institute of Veterinary Pathobiology, The Royal Veterinary and Agricultural University, Frederiksberg C, Denmark

,

Nils Brünner

¹Institute of Veterinary Pathobiology, The Royal Veterinary and Agricultural University, Frederiksberg C, Denmark

,

Ulrik Lademann

› Author Affiliations

Abstract

Summary

In a number of cancer types high tumor tissue levels of plasminogen activator inhibitor type 1 (PAI-1) protein are strongly associated with shorter cancer patient survival. This association has been intriguing since PAI-1 is known to inhibit urokinase plasminogen activator (uPA) that converts plasminogen to plasmin, which is actively involved in tumor progression and invasion. In order to further explore the biological role of PAI-1 in cancer, we have prepared fibroblasts from PAI-1 gene deficient mice and from their wild type littermates. From these fibroblasts fibrosarcoma cell lines were established and characterized. Both types of fibroblasts underwent spontaneous transformation as indicated by aneuploidy, immortalization, clonogenicity in soft agar and tumor formationin vivo. While both PAI-1 deficient and PAI-1 expressing cell lines showed similar proliferation ratesin vitro, cells devoid of PAI-1 were significantly more sensitive to apoptotic stimuli. When inoculated subcutaneously into nude mice PAI-1 expressing cells rapidly established tumors, while PAI-1 deficient cells had a significantly longer lag-phase before they started to grow (p<0.0001). The present study suggests that PAI-1,besides its uPA inhibiting function, has a role in cancer progression by protecting tumor cells from undergoing apoptosis.

Keywords

PAI-1 - murine fibrosarcoma cell lines - apoptosis

Full Text

References

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