title: Interleukin-23 is sufficient to induce rapid de novo gut tumorigenesis, independent of carcinogens, through activation of innate lymphoid cells.
abstract: Chronic inflammation has been associated with increased risk for developing gastrointestinal cancer. Interleukin-23 (IL-23) receptor signaling has been correlated with inflammatory bowel disease pathogenesis, as well as promotion of tumor growth. However, little is known about the relative potential for IL-23-directed causality in gut tumorigenesis. We report that IL-23 transgene expression was sufficient to induce rapid (3-4 weeks) de novo development of intestinal adenomas with 100% incidence. Initiation of tumorigenesis was independent of exogenous carcinogens, Helicobacter colonization, or pre-existing tumor-suppressor gene mutations. Tumorigenesis was mediated by Thy1(+)IL-23R(+) innate lymphoid cells (ILC3), in part, through IL-17 responses as tumor development was inhibited in RAG(-/-) × IL-17(-/-) double knockout mice. Remarkably, IL-23 initiation of tumorigenesis by resident ILCs consistently occurred before recruitment of conspicuous inflammatory infiltrates. Our results reveal an explicit role for IL-23-mediated initiation of gut tumorigenesis and implicate a key role for IL-23R(+) ILC3 in the absence of overt cellular infiltrate recruitment.
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: I H
authors.initials: IH
authors.lastname: Chan
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: R
authors.initials: R
authors.lastname: Jain
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Tessmer
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: D
authors.initials: D
authors.lastname: Gorman
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mangadu
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sathe
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: F
authors.initials: F
authors.lastname: Vives
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: C
authors.initials: C
authors.lastname: Moon
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: E
authors.initials: E
authors.lastname: Penaflor
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Turner
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: G
authors.initials: G
authors.lastname: Ayanoglu
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chang
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: B
authors.initials: B
authors.lastname: Basham
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Mumm
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Pierce
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Yearley
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: McClanahan
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Phillips
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Cua
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: E P
authors.initials: EP
authors.lastname: Bowman
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Kastelein
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: D
authors.initials: D
authors.lastname: LaFace
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D002273:Carcinogens; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D010641:Phenotype; D018123:Receptors, Interleukin / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002273:Carcinogens; D016207:Cytokines; D020381:Interleukin-17; D053759:Interleukin-23; D018123:Receptors, Interleukin; C528688:interleukin-23 receptor, mouse; D007371:Interferon-gamma