Barrett's esophagus and animal models

Abstract

Concise summaries Significant progress has been made in the last few decades using animal models to recreate the esophagitis–metaplasia–carcinoma sequence similar to that seen in human Barrett’s esophagus (BE) and EAC. More recent works focus on molecular pathways associated with intestinal metaplasia and carcinogenesis, as well as similarities between genetic mutations occurring in humans and animal models, mouse, rat, pig, rabbit, guinea pig, dog, cat, ferret, and possum. Despite the lack of a perfect model, there is still significant potential in using these models to clarify the contribution of different types of reflux (gastric, biliary, and pancreatic) to esophageal adenocarcinoma and to determine how the different types of refluxate interact. Refluxed duodenal contents cause gastric and esophageal carcinoma in rats without exposure to carcinogens, and several rat duodenal contents reflux models have been developed. BE in the animal models has well-developed goblet cells positive forMUC2, gastric pyloric-type mucins positive for MUC6, and sometimes intermingled with gastric foveolar-type mucins positive for MUC5AC. A gut regenerative cell lineage, characterized by pyloric–foveolar metaplasia followed by the appearance of goblet cells, occurs in the regenerative process in response to chronic inflammation. High animal-fat dietary intake causes severe obesity, resulting in the development of increased abdominal pressure and increased refluxate, particularly of the duodenal contents. The N-nitroso bile acid conjugates, which have mutagenecity, play an important role in Barrett’s carcinogenesis, and are stabilized by gastric acid. Experiments have been made in a rodent duodeno-esophageal reflux model using thioproline or cyclooxygenase-2 inhibitor to prevent the inflammation–metaplasia– adenocarcinoma sequence. Thioproline is one of the nitrite scavengers, which reduce the production of carcinogenic nitroso-compounds. Celecoxib could postpone the sequence itself, whereas thioproline could only prevent the evolution of Barrett’s esophagus to cancer. The Levrat’s surgical model of esophago-duodenal anatomosis in rats has been shown to induce gastroduodenojejunal reflux. This in vivo model reproduces the sequence of histologic and molecular events that lead to the development of BE and esophageal adenocarcinoma in humans and, as such, provides a realistic and translatable model for development of therapeutics for EAC. A pilot study using proteomics to evaluate for differentially expressed markers in the progression from metaplasia to dysplasia and ultimately adenocarcinoma in human tissues has been conducted. Differential expression of cytokeratin 20 in specimens from human patients and the Levrat’s model substantiated the hypothesis that the animal model is representative of human cancer and, hence, further supporting the basis for its utilization. Furthermore, if this data is confirmed, the Levrat’s approach may serve as a model for preclinical drug development. Up to ten potential novel ta...

Single cell RNA-seq reveals profound transcriptional similarity between Barrett’s oesophagus and oesophageal submucosal glands

“…5c ). As p63 + KRT7 + cells have been shown to generate intestinal-like epithelial cells in organoid culture upon CDX2 overexpression, it may be possible that these oesophageal cells could be related to the transitional zone progenitor cells previously observed in humans 21 .…”

“…Many of the proposed BO origin theories are based on transgenic mouse studies, and the submucosal gland cell theories are based on human histopathology studies. Unfortunately, submucosal gland theories cannot be tested in mice since mice and humans have key differences in their gastrointestinal anatomy, and rodents lack oesophageal glands 21 . These difficulties argue for an unbiased and systematic genetic approach to BO characterisation in humans with all relevant control cell types to better understand the origin of BO cell types.…”

Barretts's carcinogenesis

“…Even healthy individuals experience regurgitation of duodenal fluid into the stomach after eating, and the amount regurgitated increases in patients with GERD reportedly. Thus, lying down after eating can result in the duodenal fluid, which contains bile acids, remaining in the stomach (e.g., during sleep) . Suzuki et al .…”

“…Thus, lying down after eating can result in the duodenal fluid, which contains bile acids, remaining in the stomach (e.g., during sleep). 121 Suzuki et al 122 have reported that the cardia has the highest concentration of nitrates originating from food, which maximizes the luminal generation of N-nitroso-compounds from dietary nitrate at the most proximal cardiac region of the acidic stomach. Because the accumulated reflux fluid would contain endogenous N-nitroso-bile acids from the stomach, chronic inflammation and carcinogenesis could then occur in the esophagogastric junction or esophagus.…”

Two distinct etiologies of gastric cardia adenocarcinoma: interactions among pH, Helicobacter pylori, and bile acids

“…Gastric contents are easily pooled, and N -nitroso compounds could be generated at night, in the gastric juice with the refluxate including bile acids in the fornix located on the posterior side of the body. Moreover, both the esophagus and the proximal cardia portion are easily exposed to the N -nitroso compounds by transient lower esophageal sphincter relaxation as well as other lower esophageal sphincter pressure abnormalities in the supine position ( Macke et al, 2011 ). We reported that one of these nitroso compounds, N -nitroso glycocholic, rapidly decomposed under alkaline conditions (pH 9) [t (1/2) = 0.96 h] but remained quite stable under acidic (pH 2) [t (1/2) = 12.8 h] and neutral (pH 7) [t (1/2) = 7.8 h] conditions ( Araki et al, 2008 ).…”