Development of esophageal metaplasia and adenocarcinoma in a rat surgical model without the use of a carcinogen

Abstract

In order to establish an animal model for studying the cause and prevention of esophageal adenocarcinoma (EAC) and its frequent precursor, Barrett's esophagus (BE), factors affecting the pathogenic processes were investigated in an esophagoduodenal anastomosis model with rats. Experiments by us and others have shown that surgical treatment produced reflux esophagitis with cell hyperproliferation, but not EAC. Additional treatment with a carcinogen has been shown to be necessary for the development of EAC, squamous cell carcinomas (SCC) or EAC/SCC mixtures. We found that the surgically treated animals developed anemia due possibly to reduced iron absorption. When the operated animals were supplemented with iron, EAC occurred at a high rate (73%) after 30 weeks, and treatment with N'-nitrosonornicotine did not enhance the rate of tumorigenesis. Treatment with carcinogen, however, induced SCC in the group of rats killed after 22 weeks. The results suggest that iron overload, which is known to cause oxidative damage, is an enhancing factor for adenocarcinogenesis. The pathogenesis of EAC in the iron-supplemented, non-carcinogen treated group resembles human esophageal adenocarcinogenesis in many features. All the BE was the specialized type with goblet cells (containing sialomucin or sulfomucin) and columnar cells (containing acid or neutral mucin) as well as an incompletely developed brush border. Almost all of the BE was located at the bottom of the esophagus and was continuous with the duodenal mucosa; dysplasia became more frequent at later time points. All of the cancers were well-differentiated mucinous EAC, and most of the EAC had an adjacent area of BE with dysplasia. The results are consistent with the proposed human sequence for pathogenic events of BE progression to 'BE with dysplasia' and then to EAC. Esophagoduodenal anastomosis and iron treatment in rats produces a high rate of BE and EAC which are morphologically similar to human BE and EAC; this may be a useful animal model to study the development and prevention of EAC in humans.

Phenotype of columnar-lined esophagus in rats with esophagogastroduodenal anastomosis: similarity to human Barrett's esophagus

“…12 As described earlier, all the EACs in the rat model were well-differentiated mucinous adenocarcinomas. 5,[10][11][12] In patients with BE variably differentiated adenocarcinomas are seen. In our study, only one of 11 human EACs was of the mucinous type.…”

“…[5][6][7] When chemical carcinogens are combined with surgically induced gastroesophageal reflux of gastrointestinal contents, mixed adenosquamous carcinomas are generally produced. 8,9 Goldstein et al 10 reported that rats with esophagoduodenal anastomosis develop EAC without adenosquamous or squamous cell carcinoma, and the frequency of carcinoma development increases by correction of postoperative anemia with parenteral iron therapy. Similarly, rats surgically treated with esophagogastroduodenal anastomosis (EGDA) to induce esophageal reflux of gastric acid and bile developed columnar-lined esophagus (CLE) and EAC in over half of the animals by 40 weeks after surgery.…”

Involvement of oxidative stress in experimentally induced reflux esophagitis and Barrett’s esophagus: clue for the chemoprevention of esophageal carcinoma by antioxidants

“…The importance of antioxidants in the treatment of reflux esophagitis comes also from the reported facts that oxidative damage has long been related to carcinogenesis in human cancers and animal cancer models [26][27][28][29] and oxidative damages have been reported to be related to columnar-lined esophagus, Barrett's esophagus. Reactive oxygen species increased with the grade of esophagitis and were reported to be the highest in Barrett's esophagus [27].…”

Chronic acid exposure leads to activation of thecdx2intestinal homeobox gene in a long-term culture of mouse esophageal keratinocytes

“…Recent studies have shown that animals such as mice, rats and rabbits can provide in vivo models for intestinal metaplasia of the esophagus (Vaezi et al, 1995;Goldstein et al, 1997;Ouatu-Lascar et al, 1999;Xu et al, 2000). Apart from the anatomo-pathologic observations and the evaluation of the severity of the lesions, the molecular mechanisms underlying the metaplastic process that take place in the esophagus cannot be investigated in these models.…”