A Senescence-Inflammatory Switch from Cancer-Inhibitory to Cancer-Promoting Mechanism

Menée in vitro et in vivo, cette étude met en évidence un processus de nature inflammatoire qui, en fonction de l'activité de p53, est susceptible de réprimer ou de favoriser la tumorigenèse

Résumé en anglais

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±) 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±-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.

"Senescence induced by chronic epithelial stress invokes para-inflammation
"The senescence process takes place without p53, yet dissociates from growth arrest
"It is then a procarcinogenic inflammatory process that is blocked by NSAIDs
"A similar process that transforms epithelial organoids is reversed by NSAIDs