title: Interleukin (IL)-18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor.
abstract: Interleukin (IL)-18 is a proinflammatory and immune-enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)γ. We previously reported that IL-18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro-IL-18) in vitro. In addition, IL-18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL-18 is increased in EOC patients' sera at diagnosis as compared with age-matched healthy women. IL-18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL-18 expression in cytokeratine-positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL-18. The detection of human IL-18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL-18 is tumor-derived. However, IL-18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL-18 present in the ascitic fluid as pro-IL-18, which is biologically inactive. Accordingly, IFNγ was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL-18 levels. Altogether these data indicate that IL-18 in EOC fluids is predominantly tumor-derived and that its lack of biological activity may represent a mechanism of tumor-escape.
authors.affiliation: Department of Translational Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Orengo
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
authors.forename: Loredana
authors.initials: L
authors.lastname: Miglietta
authors.forename: Cristian
authors.initials: C
authors.lastname: Andreani
authors.forename: Milena
authors.initials: M
authors.lastname: Bruzzone
authors.forename: Andrea
authors.initials: A
authors.lastname: Puppo
authors.forename: Paolo
authors.initials: P
authors.lastname: Cristoforoni
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Centurioni
authors.forename: Marina
authors.initials: M
authors.lastname: Gualco
authors.forename: Sandra
authors.initials: S
authors.lastname: Salvi
authors.forename: Simona
authors.initials: S
authors.lastname: Boccardo
authors.forename: Mauro
authors.initials: M
authors.lastname: Truini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Piazza
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.forename: Delia
authors.initials: D
authors.lastname: Mezzanzanica
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000097:blood* / Q000276:immunology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D001202:Ascitic Fluid / Q000378:metabolism; D015153:Blotting, Western; D018284:Cystadenocarcinoma, Serous / Q000097:blood* / Q000276:immunology; D016889:Endometrial Neoplasms / Q000097:blood* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000097:blood* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood* / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D020382:Interleukin-18; D007371:Interferon-gamma