metallothionein and Esophagitis

The potential of the metal-binding protein, metallothionein, in assessing the progression of normal oesophagus through Barrett's to adenocarcinoma was investigated. Metallothionein was quantitatively determined in resected tissues from patients undergoing oesophagectomy for high grade dysplasia/adenocarcinoma and in biopsies from patients with Barrett's syndrome. In 10 cancer patients, metallothionein concentrations in adenocarcinoma were not significantly different from normal oesophagus, although six had elevated metallothionein concentrations in the metaplastic tissue bordering the adenocarcinoma. In 17 out of 20 non-cancer patients with Barrett's epithelium, metallothionein was significantly increased by 108% (P<0.004). There was no association between the metallothionein levels in Barrett's epithelium and the presence of inflammatory cells, metaplasia or dysplasia. Metallothionein is a marker of progression from normal to Barrett's epithelium but is not increased in oesophageal adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Barrett Esophagus; Biomarkers; Biomarkers, Tumor; Biopsy; Disease Progression; Esophageal Neoplasms; Esophagitis; Esophagus; Female; Gastroesophageal Reflux; Humans; Hyperplasia; Male; Metallothionein; Metaplasia; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; Precancerous Conditions

Oxidative damage has long been related to carcinogenesis in human cancers and animal cancer models. Recently a rat esophageal adenocarcinoma (EAC) model was established in our laboratory by using esophagoduodenal anastomosis (EDA) plus iron supplementation. Our previous study suggested that iron supplementation enhanced inflammation and the production of reactive nitrogen species in the esophageal epithelium, which could contribute to esophageal adenocarcinogenesis. Here we further characterized oxidative damage in this model. We were particularly interested in how excess iron was deposited in the esophagus, and which cells were targeted by oxidative damage. Male Sprague-Dawley rats received iron supplementation (50 mg Fe/kg/month, i.p.) starting 4 weeks after EDA. The animals were killed at 11, 30 or 35 weeks after surgery. EAC appeared as early as week 11 after surgery, and increased over time, up to 60% at 35 weeks after surgery. All EACs were well-differentiated mucinous adenocarcinoma at the squamocolumnar junction. Iron deposition was found at the squamocolumnar junction and in the area with esophagitis. Esophageal iron overload could result from transient increase of blood iron after i.p. injection, and the overexpression of transferrin receptor in the premalignant columnar-lined esophagus (CLE) cells. Oxidative damage to DNA (8-hydroxy-2'-deoxyguanosine), protein (carbonyl content) and lipid (thiobarbituric acid reactive substance) in the esophagus was significantly higher than that of the non-operated control. CLE cells were believed to be the target cells of oxidative damage because they overexpressed heme oxygenase 1 and metallothionein, both known to be responsive to oxidative damage. We propose that oxidative damage plays an important role in the formation of EAC in the EDA model, and a similar situation may occur in humans with gastroesophageal reflux and iron over-nutrition.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma, Mucinous; Anastomosis, Surgical; Animals; Barrett Esophagus; Cocarcinogenesis; Deoxyguanosine; Disease Models, Animal; DNA Adducts; Duodenum; Epithelial Cells; Esophageal Neoplasms; Esophagitis; Esophagus; Gastroesophageal Reflux; Heme Oxygenase (Decyclizing); Humans; Iron; Isoenzymes; Male; Metallothionein; Oxidative Stress; Postoperative Complications; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Transferrin; Thiobarbituric Acid Reactive Substances