Esophageal Adenocarcinoma in “Mice and Men”: Back to Basics!

Abstract

Adenocarcinoma related to Barrett's esophagus (BE) is increasing in the West faster than any other cancer. There are many potential chemopreventive agents as well as predictive biomarkers of cancer progression, but what is required is a robust high-throughput model in which to test hypotheses preclinically. The pathophysiology of metaplasia and cancer has been studied in 10 animal species. Though they have considerable genetic divergence, anatomical dissimilarity, and experimental flaws, they have provided some data to test in the clinic, especially relating to activation of common genetic pathways, role of hypergastrinemia, and duodenogastric reflux in cancer progression. In this regard, the human postesophagectomy model, which has a 30% recurrence of BE within 3 yr and a 5% recurrence of adenocarcinoma over 10 yr, is now being utilized to understand how human metaplasia occurs. Furthermore, improved clinical trial designs mean that more sophisticated questions can be addressed in man.

Long-term proton pump induced hypergastrinaemia does induce lineage-specific restitution but not clonal expansion in benign Barrett's oesophagus in vivo

“…Moreover, there is a suggestion that PPI therapy may actually increase the generation of Barrett's oesophagus in a proportion of patients 7–9. This latter theory is further supported by animal studies which, despite their flaws, have been consistent in pointing to an increased propensity of oesophageal adenocarcinoma (EAC) with PPI use 10 11. In this regard, gastrin, in its various forms (preprogastrin, progastrin and the main mature forms gastrin 34, gastrin 17 and gastrin 14) all have biological activity in the gastrointestinal (GI) tract.…”

Reply to Letter to the Editor: Re: Comparison of COX-2, Ki-67, and BCL-2 expression in normal esophageal mucosa, Barrett’s esophagus, dysplasia, and adenocarcinoma with postablation mucosa and implications for ablative therapies (Online First)

“…We note that the cited study relating the higher levels of COX-2 expression and prostaglandin E2 with esophageal H. pylori colonization was based purely on an animal model [15]. Despite the various organic similarities between such animals and humans, including the activation of common genetic pathways, role of hypergastrinemia, and duodenogastric reflux in cancer progression, such animal studies do not necessarily reflect the equivalent pattern of human disease [16]. Indeed, H. pylori infection has been shown to contribute to gastric carcinogenesis but any potential role in esophageal disease, including BO, is still controversial.…”

A Mouse Model for Barrett’s Esophagus: Surgery and Histology

“…For this purpose, several animal models have been developed, however none of them is devoid of some weakness [4]. Indeed, the ideal animal model should encompass all the steps between BE and EA, also modelling the chronic inflammation which underlies any step of esophageal carcinogenesis [5].…”