title: Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis.
abstract: Interleukin (IL)-21 triggers inflammatory signals that contribute to the growth of neoplastic cells in mouse models of colitis-associated colorectal cancer (CRC). Because most CRCs are sporadic and arise in the absence of overt inflammation we have investigated the role of IL-21 in these tumors in mouse and man. IL-21 was highly expressed in human sporadic CRC and produced mostly by IFN-γ-expressing T-bet/RORγt double-positive CD3+CD8- cells. Stimulation of human CRC cell lines with IL-21 did not directly activate the oncogenic transcription factors STAT3 and NF-kB and did not affect CRC cell proliferation and survival. In contrast, IL-21 modulated the production of protumorigenic factors by human tumor infiltrating T cells. IL-21 was upregulated in the neoplastic areas, as compared with non-tumor mucosa, of Apc(min/+) mice, and genetic ablation of IL-21 in such mice resulted in a marked decrease of both tumor incidence and size. IL-21 deficiency was associated with reduced STAT3/NF-kB activation in both immune cells and neoplastic cells, diminished synthesis of protumorigenic cytokines (that is, IL-17A, IL-22, TNF-α and IL-6), downregulation of COX-2/PGE2 pathway and decreased angiogenesis in the lesions of Apc(min/+) mice. Altogether, data suggest that IL-21 promotes a protumorigenic inflammatory circuit that ultimately sustains the development of sporadic CRC.
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: De Simone
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ronchetti
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Franzè
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Colantoni
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Ortenzi
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Massimo C
authors.initials: MC
authors.lastname: Fantini
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Angelamaria
authors.initials: A
authors.lastname: Rizzo
authors.affiliation: Department of Surgery, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Giuseppe S
authors.initials: GS
authors.lastname: Sica
authors.affiliation: Department of Surgery, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Sileri
authors.affiliation: Department of Surgery, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Rossi
authors.affiliation: Centre for Immunology and Infectious Disease, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, UK.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: MacDonald
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Stolfi
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D048708:Cell Growth Processes / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000473:pathology; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology*; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D016898:Interferon-alpha / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000276:immunology; D015398:Signal Transduction; D000098546:Interleukin-21
chemical_list: D016898:Interferon-alpha; D007378:Interleukins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D000098546:Interleukin-21
keywords: Apcmin/+ mice; COX-2/PGE2; STAT3; VEGF
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