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 target regimens identified and selected through the proteomics screen will be tested in a multi-arm study in rats.