Interaction of Muc2 and Apc on Wnt Signaling and in Intestinal Tumorigenesis: Potential Role of Chronic Inflammation

Abstract

Somatic mutations of the adenomatous polyposis coli (APC) gene are initiating events in the majority of sporadic colon cancers. A common characteristic of such tumors is reduction in the number of goblet cells that produce the mucin MUC2, the principal component of intestinal mucus. Consistent with these observations, we showed that Muc2 deficiency results in the spontaneous development of tumors along the entire gastrointestinal tract, independently of deregulated Wnt signaling. To dissect the complex interaction between Muc2 and Apc in intestinal tumorigenesis and to elucidate the mechanisms of tumor formation in Muc2 À/À mice, we crossed

A Novel Mouse Model of Inflammatory Bowel Disease Links Mammalian Target of Rapamycin-Dependent Hyperproliferation of Colonic Epithelium to Inflammation-Associated Tumorigenesis

“…The depletion of goblet cells is interesting in light of the fact that genetic ablation of this lineage and the mucin they produce leads to tumor formation associated with an inflammatory response. 28,29 In addition, using an antibody that recognizes the endothelial cell-specific marker, CD31, we observed a markedly increased vessel density in the inflamed colon in Stat3-IKO mice (Figure 4, H versus I), suggesting increased angiogenesis in the inflamed tissue. Overall, these findings indicate a significant alteration of homeostasis of the colonic epithelium within the large intestine of the Stat3-IKO mice, including a marked increase in proliferating epithelial cells and a loss of colonic epithelial differentiation.…”

Mucin‐depleted foci show strong activation of inflammatory markers in 1,2‐dimethylhydrazine‐induced carcinogenesis and are promoted by the inflammatory agent sodium dextran sulfate

“…43 On the other hand, it has also been demonstrated that lack of Muc2 increases colon carcinogenesis in mice and causes a gene-expression profile associated with low levels of chronic inflammation. 10,11 Given these considerations, we can suggest that in MDF, Wnt activation caused by genetic mutations, on the one hand increases i-NOS expression, and on the other hand downregulates MUC2. The resulting defect in mucin production thus exposes MDF and the associated stroma to luminal inflammatory stimuli, which in turn may activate subepithelial macrophages localized on the surface area to produce PGE2, reinforcing the activation of Wnt signalling in MDF-colonocytes in a paracrine fashion.…”

“…[6][7][8][9] Interestingly, it has also been demonstrated that Muc2-deficient mice are prone to intestinal carcinogenesis and that the introduction of a mutant Muc2 allele into Apc-mutated mice greatly increases the transformation induced by Apc mutation. 10,11 Given these considerations and the fact that MDF represent one of the earliest stages of colon carcinogenesis, we thought it interesting to study inflammation in MDF. Therefore, we studied with immunohistochemistry (IH) the expression of COX-2, inducible nitric oxide synthase (i-NOS), NO-tyrosine (NO-tyr) and macrophage infiltration in MDF induced in rats by the colon carcinogen 1,2 dimethylhydrazine (DMH).…”

Novel cell culture model for prevention of carcinogenic risk in familial adenomatous polyposis syndrome

“…The genetically predisposed animal models for FAP syndrome exhibit high incidence of adenoma predominantly in the small intestine, rather than in the colon (10)(11)(12). However, genetic manipulation of the Apc mutant mouse through crosses with BubR1 +/-(17), Smad-3 (18), ER-· +/-, ER-ß +/-and ER-ß -/- (19), Fabpl-Cre/Apc-lox-p conditional truncated Apc mice (20) and Muc2 (21) has been demonstrated to specifically accelerate colon carcinogenesis. Thus, reliable colon cell culture model with Apc mutation and quantifiable carcinogenic risk should provide an alternative approach complementing the existing preclinical genetically predisposed animal models.…”