Host factors influence Barrett’s carcinogenesis: findings from a mouse gastroduodenal reflux model

Abstract

Background Rat gastroduodenal reflux models have been used for analyzing Barrett’s carcinogenesis. Mice seem to be more useful than rats for studies targeting genes. Methods We induced gastroduodenal contents reflux by esophagojejunostomy using C57BL/6J mice. Mice were divided into a standard diet and high-fat diet groups and kept for 60 weeks. Bile was sampled from the gallbladder to analyze bile acid fractions, and the esophagus was removed for a histological investigation. Human esophagogastric junction adenocarcinoma cells (OE19) were exposed to taurocholic acid (TCA), after which cell proliferative activity was measured. Rat esophageal cancer cell lines, ESCC-DR and ESCC-DRtca with higher malignant potential induced by continuous TCA exposure, were used to perform comprehensive genetic analysis (CGH). Results Barrett’s epithelium onset occurred in all mice, and no differences in histological changes were noted between the standard diet and high-fat diet groups. However, no development of adenocarcinoma was noted. Most of the mouse bile acid was taurine conjugates. In the experiment using OE-19 cells, TCA promotes cell proliferation in a dose-dependent manner. Array CGH analysis revealed a large number of chromosomal abnormalities in the ESCC-DR, in addition to genetic abnormalities such as in the UGT2B gene, the substrate of which is bile acid. TCA administration resulted in more chromosomal abnormalities being detected. Conclusions We showed the effects of TCA in cancer progression in vitro. However, Barrett’s adenocarcinoma onset rates differ between mice and rats despite undergoing similar reflux stimulation including taurine-conjugated bile acids being detected in mouse bile juice. These results suggest that host factors seem to influence Barrett’s carcinogenesis.

The role of bile acids in the development of Barrett’s Oesophagus and Oesophageal Adenocarcinoma: a systematic review

“…Eleven studies examined the effect of BAs on proliferation (51,60,62,(66)(67)(68)(72)(73)(74)(75)(76)(77)(78), see Table 4. Four were human studies (60,62,66,77) and seven were carried out in human cell-lines (68,(72)(73)(74)(75)(76)78). Two studies were carried out on non-malignant oesophageal cells (66,72), four were carried out on BO (60,62,73,77) and five on OAC (68,(74)(75)(76)78).…”

“…Eleven studies examined the effect of BAs on proliferation (51,60,62,(66)(67)(68)(72)(73)(74)(75)(76)(77)(78), see Table 4. Four were human studies (60,62,66,77) and seven were carried out in human cell-lines (68,(72)(73)(74)(75)(76)78).…”

“…Four were human studies (60,62,66,77) and seven were carried out in human cell-lines (68,(72)(73)(74)(75)(76)78). Two studies were carried out on non-malignant oesophageal cells (66,72), four were carried out on BO (60,62,73,77) and five on OAC (68,(74)(75)(76)78). The effects of DCA were examined in four studies (62,68,76,77).…”

Proposal for an Organ-Specific Chronic Inflammation–Remodeling–Carcinoma Sequence

“…Chronic exposure of the esophageal mucosa to gastroduodenal fluid (bile salts and hydrochloric acid) causes active and erosive esophagitis, resulting in metaplasia of squamous cells to columnar epithelial cells, and submucosal fibrosis as Barrett's esophagus. It has been shown that chronic gastroesophageal reflux induces Barrett's esophagus according to clinicopathological analyses [5,6] and experimental studies using animal models [7][8][9][10]. Regarding the requirement of goblet cells (intestinal metaplasia) within the columnar-lined mucosa, the global histological definition of Barrett's esophagus is still controversial in Europe, the US, the UK and Japan [5] (Figure 2).…”

Roles of the hexosamine biosynthetic pathway and pentose phosphate pathway in bile acid‐induced cancer development

“…We selected taurocholic acid (TCA) among various bile acids to stimulate ESCC cells because of the following 5 reasons: (i) in cases with Barrett's esophagus/stricture, taurine conjugates are predominant in the esophagus; (ii) increased proportions of taurine conjugates due to a high‐fat diet influence Barrett's carcinogenesis in reflux models; (iii) exposure to TCA promotes cell proliferation in a dose‐dependent manner in an experiment using E‐G junction cancer cells (OE‐19); (iv) chronic exposure to TCA causes tumor progression in ESCC cells; and (v) acid and bile acids induce NF‐κB pathway signaling in esophageal squamous cells in gastroesophageal reflux disease . In addition, TCA significantly increased protein levels of p‐NF‐κB (p65) in both a time‐dependent and dose‐dependent manner, and TCA significantly increased nuclear translocation of NF‐κB (p65) in a human cholangiocarcinoma cell line…”