title: Indication of a role of plasminogen activator inhibitor type I in protecting murine fibrosarcoma cells against apoptosis.
abstract: 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 formation in vivo. While both PAI-1 deficient and PAI-1 expressing cell lines showed similar proliferation rates in 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.
authors.affiliation: Institute of Veterinary Pathobiology, The Royal Veterinary and Agricultural University, Frederiksberg C, Denmark.
authors.forename: Maria Unni
authors.initials: MU
authors.lastname: Rømer
authors.forename: Anne
authors.initials: A
authors.lastname: Kirkebjerg Due
authors.forename: Jørgen
authors.initials: J
authors.lastname: Knud Larsen
authors.forename: Kenneth Francis
authors.initials: KF
authors.lastname: Hofland
authors.forename: Ib Jarle
authors.initials: IJ
authors.lastname: Christensen
authors.forename: Peter
authors.initials: P
authors.lastname: Buhl-Jensen
authors.forename: Kasper
authors.initials: K
authors.lastname: Almholt
authors.forename: Ole
authors.initials: O
authors.lastname: Lerberg Nielsen
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Ulrik
authors.initials: U
authors.lastname: Lademann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005354:Fibrosarcoma / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism*; D012983:Soft Tissue Neoplasms / Q000473:pathology / Q000503:physiopathology*
chemical_list: D017395:Plasminogen Activator Inhibitor 1