| The goal of this dissertation research is to elucidate the mechanisms for the development of esophageal adenocarcinoma (EAC). With two animal models, I tested the hypothesis that oxidative stress is a major causative factor in the development of rat EAC and its premalignant lesion, columnar-lined esophagus (CLE). Both animal models, esophagoduodenal anastomosis (EDA) and esophagogastroduodenal anastomosis (EGDA), produced mucinous EAC, and the carcinogenesis was greatly enhanced by supplementation with iron dextran. In EDA rats supplemented 50mg Fe/kg/month via i.p. injection, esophageal iron overload was due to a transient increase in blood iron after i.p. injection, and the overexpression of transferrin receptor in CLE. Oxidative damage to DNA, protein and lipid in the esophagus of EDA rat was significantly higher than that of the non-operated control. CLE cells were believed to be the target cells of oxidative damage since they overexpressed heme oxygenase 1 and metallothionein, both known to be responsive to oxidative damage. At 40 weeks after EDA with 12 mg Fe/kg/wk i.p. injection, dietary selenium increased the incidence of EAC and the tumor volume, while vitamin E inhibited carcinogenesis, especially in the selenium-supplemented group.;To overcome the problem of malnutrition due to EDA, EGDA was established by anastomosing the duodenum to the gastroesophageal junction. EGDA rats had normal nutritional status, and mild esophagitis. However, the area surrounding the anastomosis opening showed more severe esophagitis. The incidence of EAC increased from 25.6% to 53.7% in the group received iron supplementation (4 mg Fe/kg/wk i.p.). All the tumors were well-differentiated mucinous adenocarcinomas at the squamocolumnar junction. The junction area was the site with most of the iron deposition. Using samples obtained of EGDA rats, I also compared gene expression patterns between EAC tumor and normal tissue by protein two-dimensional gel electrophoresis and cDNA expression array. EAC had a marked overexpression of grp94 which showed an increased expression in goblet cells during the progression from duodenum to CLE and EAC. This correlated with an increase of 8-hydroxydeoxyguanosine, apoptotic index, and proliferative index.;In this thesis research, I have further characterized the EDA model and developed the EGDA model. The results of my study provided evidence for the hypothesis that oxidative stress plays an important role in the formation of rat EAC. Oxidative stress induces hyperproliferation, DNA damage and apoptosis. This protective effect of grp94 overexpression may provide the columnar cells in CLE with the ability to survive oxidative stress and apoptosis leading to the development of EAC. A similar situation may occur in humans with gastroesophageal reflux, especially when combined with iron over-nutrition. |
