TY - JOUR
T1 - A Senescence-Inflammatory Switch from Cancer-Inhibitory to Cancer-Promoting Mechanism
AU - Pribluda, Ariel
AU - Elyada, Ela
AU - Wiener, Zoltan
AU - Hamza, Haya
AU - Goldstein, Robert E.
AU - Biton, Moshe
AU - Burstain, Ido
AU - Morgenstern, Yael
AU - Brachya, Guy
AU - Billauer, Hana
AU - Biton, Sharon
AU - Snir-Alkalay, Irit
AU - Vucic, Domagoj
AU - Schlereth, Katharina
AU - Mernberger, Marco
AU - Stiewe, Thorsten
AU - Oren, Moshe
AU - Alitalo, Kari
AU - Pikarsky, Eli
AU - Ben-Neriah, Yinon
N1 - 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.
PY - 2013/8/12
Y1 - 2013/8/12
N2 - 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 (CKI alpha) 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 CKI alpha-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.
AB - 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 (CKI alpha) 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 CKI alpha-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.
UR - http://www.scopus.com/inward/record.url?scp=84881526073&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2013.06.005
DO - 10.1016/j.ccr.2013.06.005
M3 - مقالة
C2 - 23890787
SN - 1535-6108
VL - 24
SP - 242
EP - 256
JO - Cancer Cell
JF - Cancer Cell
IS - 2
ER -
SDG 3 Good Health and Well-being