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.

Type I Interferons Control Proliferation and Function of the Intestinal Epithelium

“…Importantly, ablation of either p53 or p21 CIP1/WAF1 in CK1␣-deficient animals led to the development of malignant tumors (37,38). However, we did not observe these tumors in any groups of CK1␣/IFNAR1-deficient mice that developed a lethal disruption of intestinal barrier function (Fig.…”

“…The restriction of proliferation of Csnk1a1-deficient IECs could be lifted by the concurrent inactivation of either p53, p21 CIP1/WAF1 (37,38), or, to a lesser extent, IFNAR1 (this work). Importantly, ablation of either p53 or p21 CIP1/WAF1 in CK1␣-deficient animals led to the development of malignant tumors (37,38).…”

“…Priming phosphorylation of ␤-catenin by CK1␣ greatly increases the phosphorylation of the ␤-catenin degron by glycogen synthase kinase 3␤ (GSK3␤) (30,31) that is required for its recognition by the ␤Trcp E3 ubiquitin ligases and subsequent ubiquitination and proteasomal degradation (32)(33)(34)(35)(36). Our recent studies demonstrated that gut-specific knockout of the Csnk1a1 gene that encodes CK1␣ leads to robust stabilization of ␤-catenin and activation of Wnt target genes (37,38). Intriguingly, ablation of Csnk1a1 alone did not lead to either epithelial cell hyperproliferation or tumorigenesis.…”

“…Instead, inactivation of CK1␣ induced the DNA damage response (DDR) and p53/p21-dependent senescence. These events appear to prevent tumorigenesis driven by hyperactive ␤-catenin because the concurrent ablation of CK1␣ with either p53 or p21 resulted in hyperproliferation and a rapid development of aggressive and invasive intestinal tumors (37,38).…”

Relationship between Obesity, Gut Microbiome and Hepatocellular Carcinoma Development

“…results], in contrast to the HCC arising in mice treated with DEN plus CCl 4 [35]. Moreover, it has recently been shown that the senescence-associated inflammatory response suppresses or promotes tumorigenesis, depending on the p53 gene status [36]. Thus, it is possible that these seemingly disparate results may reflect, at least in part, the status of the p53 gene in hepatocytes, although there are many other reconciliations, including gross differences in the models employed (obesity vs. chemical liver injury) linked to likely differences in spatial and temporal activation of SASP and qualitative and quantitative composition of the SASP.…”