The molecular landscape of colitis-associated carcinogenesis

Abstract

In spite of the well-established histopathological phenotyping of IBD-associated preneoplastic and neoplastic lesions, their molecular landscape remains to be fully elucidated. Several studies have pinpointed the initiating role of longstanding/relapsing inflammatory insult on the intestinal mucosa, with the activation of different pro-inflammatory cytokines (TNF-α, IL-6, IL-10, IFN-γ), chemokines and metabolites of arachidonic acid resulting in the activation of key transcription factors such as NF-κB. Longstanding inflammation may also modify the intestinal microbiota, prompting the overgrowth of genotoxic microorganisms, which may act as further cancer promoters. Most of the molecular dysregulation occurring in sporadic colorectal carcinogenesis is documented in colitis-associated adenocarcinoma too, but marked differences have been established in both their timing and prevalence. Unlike sporadic cancers, TP53 alterations occur early in IBD-related carcinogenesis, while APC dysregulation emerges mainly in the most advanced stages of the oncogenic cascade. From the therapeutic standpoint, colitis-associated cancers are associated with a lower prevalence of KRAS mutations than the sporadic variant. Epigenetic changes, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, are significantly involved in colitis-associated cancer development and progression. The focus now is on identifying diagnostic and prognostic biomarkers, with a view to ultimately designing patient-tailored therapies.

Dancing from bottoms up – Roles of the POZ-ZF transcription factor Kaiso in Cancer

“…We expanded our studies into the effect of Kaiso overexpression on intestinal homeostasis by crossing our Kaiso Tg/+ mice with Apc Min/+ mice [16, 49]. Consistent with earlier studies by Prokhortchouk et al ., Kaiso Tg/+ :Apc Min/+ mice exhibited significantly reduced lifespans and an approximately 3-fold increase in polyp number relative to control mice [49].…”

“…While Kaiso overexpression alone was not sufficient to drive the development of tumors in the murine intestine, Kaiso Tg/+ mice developed crypt hyperplasia and chronic intestinal inflammation [46], which is an established risk factor for CRC. In fact, in patients with inflammatory bowel disease, the cumulative risk of developing colitis-associated cancer (CAC) ranges between 18–20% [16]. The development of chronic intestinal inflammation in Kaiso overexpressing mice is intriguing on two fronts.…”

“…The development of chronic intestinal inflammation in Kaiso overexpressing mice is intriguing on two fronts. First, in contrast to sporadic CRC, Apc mutation occurs only in advanced stages of IBD- associated carcinogenesis if at all [16], which suggests a Wnt-independent mechanism by which Kaiso may promote intestinal tumorigenesis. Secondly, it suggests opposing roles for Kaiso (pro-) and p120 ctn (anti-) in intestinal inflammation/tumorigenesis since limited ablation of p120 ctn in murine intestines induced an inflammatory response characterized by an epithelial barrier defect with infiltrating neutrophils [47, 48], and promoted intestinal adenomas [48].…”

“…Notably, Wnt target gene expression was increased rather than decreased in both Kaiso Tg/+ and Kaiso Tg/+ :Apc Min/+ mice; however the increases noted in Kaiso Tg/+ mice compared to control mice were not significant [16, 49]. We also observed that increased Kaiso expression positively correlates with tumor stage in a human CRC tissue microarray (TMA) [49] and analysis of publicly available CRC microarray datasets revealed a statistically significant positive correlation between increased Kaiso expression and colon tumor tissues compared to normal tissues [16, 49], in contrast to the Prokhortchouk study [32]. Collectively, these studies indicate that in mammalian models, Kaiso promotes rather than suppresses tumorigenesis as was initially anticipated based on our findings regarding Kaiso and Wnt signalling in Xenopus .…”

“…Indeed, most studies to date have reported on Kaiso’s transcriptional repression of target genes including E-cadherin [13, 14], Wnt 11 [4], matrilysin [15], HIF1A [16], CDKN2A [17], miR-31 [18] and the miR-200 family [19]. While fewer studies have reported on Kaiso-mediated transcriptional activation of target genes [20, 21], recent studies suggest that transcriptional activation may be Kaiso’s preferred mode of transcriptional regulation.…”