title: Urokinase-type plasminogen activator deficiency promotes neoplasmatogenesis in the colon of mice.
abstract: Urokinase-type plasminogen activator (uPA) participates in cancer-related biologic processes, such as wound healing and inflammation. The present study aimed to investigate the effect of uPA deficiency on the long-term outcome of early life episodes of dextran sodium sulfate (DSS)-induced colitis in mice. Wild-type (WT) and uPA-deficient (uPA(-/-)) BALB/c mice were treated with DSS or remained untreated. Mice were necropsied either 1 week or 7 months after DSS treatment. Colon samples were analyzed by histopathology, immunohistochemistry, ELISA, and real-time polymerase chain reaction. At 7 months, with no colitis evident, half of the uPA(-/-) mice had large colonic polypoid adenomas, whereas WT mice did not. One week after DSS treatment, there were typical DSS-induced colitis lesions in both WT and uPA(-/-) mice. The affected colon of uPA(-/-) mice, however, had features of delayed ulcer re-epithelialization and dysplastic lesions of higher grade developing on the basis of a significantly altered mucosal inflammatory milieu. The later was characterized by more neutrophils and macrophages, less regulatory T cells (Treg), significantly upregulated cytokines, including interleukin-6 (IL-6), IL-17, tumor necrosis factor-α, and IL-10, and lower levels of active transforming growth factor-β1 (TGF-β1) compared to WT mice. Dysfunctional Treg, more robust protumorigenic inflammatory events, and an inherited inability to produce adequate amounts of extracellular active TGF-β1 due to uPA deficiency are interlinked as probable explanations for the inflammatory-induced neoplasmatogenesis in the colon of uPA(-/-) mice.
authors.affiliation: Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Elisavet
authors.initials: E
authors.lastname: Karamanavi
authors.affiliation: Laboratory of Biochemistry and Toxicology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Katerina
authors.initials: K
authors.lastname: Angelopoulou
authors.affiliation: Laboratory of Physiology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Sophia
authors.initials: S
authors.lastname: Lavrentiadou
authors.affiliation: Laboratory of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Tsingotjidou
authors.affiliation: Department of Agricultural Development, Democritus University of Thrace, Orestiada, Greece.
authors.forename: Zaphiris
authors.initials: Z
authors.lastname: Abas
authors.affiliation: Laboratory of Physiology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Taitzoglou
authors.affiliation: Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Vlemmas
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Suzan E
authors.initials: SE
authors.lastname: Erdman
authors.affiliation: Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece. Electronic address: teoput@vet.auth.gr.
authors.forename: Theofilos
authors.initials: T
authors.lastname: Poutahidis