A Senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism

Ariel Pribluda, Ela Elyada, Zoltan Wiener, Haya Hamza, Robert E. Goldstein, Moshe Biton, Ido Burstain, Yael Morgenstern, Guy Brachya, Hana Billauer, Sharon Biton, Irit Snir-Alkalay, Domagoj Vucic, Katharina Schlereth, Marco Mernberger, Thorsten Stiewe, Moshe Oren, Kari Alitalo, Eli Pikarsky, Yinon Ben-Neriah*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

185 Scopus citations

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 exvivo, 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.

Original languageAmerican English
Pages (from-to)242-256
Number of pages15
JournalCancer Cell
Volume24
Issue number2
DOIs
StatePublished - 12 Aug 2013

Bibliographical note

Funding Information:
This work was supported by grants from the Israel Science Foundation-Centers of Excellence, the European Research Council within the FP-7: LIVERMICROENV (to E.P.), P73CANCER (to T.S.), and PICHO (to Y.B.-N.); the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the I-CORE program of ISF (grant no. 41/11); the Israel Cancer Research fund; the Alvarez Family award; the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum; the ERC Marie Curie Program and the Sigrid Juselius Foundation (to Z.W. and K.A.); and Israeli’s Ministry of Science, Culture and Sport. We thank Eva and George Klein for helpful insights clarifying our thoughts and terminology.

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