title: A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism.
abstract: Senescence, perceived as a cancer barrier, is paradoxically associated with inflammation, which promotes tumorigenesis. Here, we characterize a distinct low-grade inflammatory process in stressed epithelium that is related to para-inflammation; this process either represses or promotes tumorigenesis, depending on p53 activity. Csnk1a1 (CKIα) downregulation induces a senescence-associated inflammatory response (SIR) with growth arrest in colorectal tumors, which loses its growth control capacity in the absence of p53 and instead, accelerates growth and invasiveness. Corresponding processes occur in CKIα-deleted intestinal organoids, assuming tumorigenic transformation properties ex vivo, upon p53 loss. Treatment of organoids and mice with anti-inflammatory agents suppresses the SIR and prevents p53-deficient organoid transformation and mouse carcinogenesis. SIR/para-inflammation suppression may therefore constitute a key mechanism in the anticarcinogenic effects of nonsteroidal anti-inflammatory drugs.
authors.affiliation: The Lautenberg Center for Immunology, Institute of Medical Research, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Pribluda
authors.forename: Ela
authors.initials: E
authors.lastname: Elyada
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Wiener
authors.forename: Haya
authors.initials: H
authors.lastname: Hamza
authors.forename: Robert E
authors.initials: RE
authors.lastname: Goldstein
authors.forename: Moshe
authors.initials: M
authors.lastname: Biton
authors.forename: Ido
authors.initials: I
authors.lastname: Burstain
authors.forename: Yael
authors.initials: Y
authors.lastname: Morgenstern
authors.forename: Guy
authors.initials: G
authors.lastname: Brachya
authors.forename: Hana
authors.initials: H
authors.lastname: Billauer
authors.forename: Sharon
authors.initials: S
authors.lastname: Biton
authors.forename: Irit
authors.initials: I
authors.lastname: Snir-Alkalay
authors.forename: Domagoj
authors.initials: D
authors.lastname: Vucic
authors.forename: Katharina
authors.initials: K
authors.lastname: Schlereth
authors.forename: Marco
authors.initials: M
authors.lastname: Mernberger
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stiewe
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.forename: Yinon
authors.initials: Y
authors.lastname: Ben-Neriah
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000473:pathology*; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal