Deoxycholic acid promotes the growth of colonic aberrant crypt foci

Abstract

AKR/J mice are resistant to the tumorigenic properties of the colon carcinogen, azoxymethane (AOM). Following AOM exposure, limited numbers of preneoplastic lesions, referred to as aberrant crypt foci (ACF), are formed in the colon, and their progression to tumors rarely occurs. To determine whether genetic resistance can be overcome by exposure to a dietary tumor promoter, AOM-exposed AKR/J mice were fed a diet containing 0.25% deoxycholic acid (DCA). DCA exposure was begun 1 wk prior to or 1 wk after tumor initiation with AOM. Mice placed on the DCA diet prior to AOM treatment developed a significantly higher multiplicity of ACF compared to AOM-exposed mice fed a control diet (15.50 +/- 0.96 vs. 6.17 +/- 0.48, respectively; P < 0.05). When DCA exposure was begun after AOM treatment (post-initiation), ACF formation was further enhanced (34.00 +/- 1.22). Interestingly, increased numbers of ACF were associated with the presence of nuclear beta-catenin, assessed by immunohistochemistry. While approximately 33% of ACF from mice exposed to DCA prior to AOM treatment contained positive nuclear beta-catenin staining, approximately 77% of ACF from mice fed DCA after AOM were positive. Accumulation of nuclear beta-catenin was not associated with a loss of E-cadherin from the plasma membrane, although loss of APC staining was a consistent feature of most AOM-induced ACF, regardless of DCA exposure. These results demonstrate that exposure to DCA, an important digestive component, is sufficient to sensitize the resistant AKR/J colon to formation of high-grade dysplasia, and that nuclear translocation of beta-catenin may play an important role in this process.

Genetic Deletion of mPGES-1 Suppresses Intestinal Tumorigenesis

“…Azoxymethane induces large numbers of ACF and adenocarcinomas that are confined to the distal colon. In addition, because there is a gradual loss of Apc, the role of PGE 2 in h-catenin signaling can be evaluated during ACF formation (21,(30)(31)(32). Our results showed that loss of mPGES-1 significantly reduced ACF size, suggesting that promotion associated with PGE 2 can also occur early during tumorigenesis.…”

“…PGE 2 has been shown to play a role in the indirect activation of hcatenin via inactivation of Axin and glycogen synthase kinase 3h (GSK-3h), proteins that form part of the h-catenin degradation complex (29). Unlike the complete loss of Apc function that occurs in Apc D14/+ -derived adenomas, the loss of Apc protein is a gradual process following azoxymethane treatment, accompanied by increased cytoplasmic and nuclear staining of h-catenin (21,(30)(31)(32).…”

Helicobacter hepaticus Infection Promotes Colon Tumorigenesis in the BALB/c- Rag2 −/− Apc Min /+ Mouse

“…Alternatively, H. hepaticus infection may promote colon tumors indirectly by modulating a carcinogenic factor in the colon. For example, human (3) and rodent (15,46,51) data suggest that secondary bile acids (deoxycholic acid and lithocholic acid) promote colon tumors. H. hepaticus may increase levels of secondary bile acids in the colon by increasing production of primary bile salts by the liver, by adversely affecting bile acid absorption from the distal ileum, and/or by modifying the large intestine bacterial microbiota in a manner that affects the activation and/or availability of secondary bile acids.…”

In Vivo Magnetic Resonance Imaging to Detect Biliary Excretion of 19F-Labeled Drug in Mice

“…These ASBT inhibitors include HMG-CoA inhibitors (statins) and dihydropyridine calcium-channel blockers; statins and calcium-channel blockers are among the most commonly prescribed drugs in the United States. Inhibition of the ASBT results in reduced intestinal uptake of bile acids and increased fecal bile acid concentrations, risk factors for colon pathology, including cancer (Flynn et al, 2007). Hence, side effects deriving from drug-induced inhibition of the ASBT could pose potential, currently unappreciated, risk.…”