title: Oxidative damage in an esophageal adenocarcinoma model with rats.
abstract: 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.
authors.affiliation: Laboratory for Cancer Research, College of Pharmacy, Rutgers University, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: Y W
authors.initials: YW
authors.lastname: Ding
authors.forename: G y
authors.initials: Gy
authors.lastname: Yang
authors.forename: F
authors.initials: F
authors.lastname: Bondoc
authors.forename: M J
authors.initials: MJ
authors.lastname: Lee
authors.forename: C S
authors.initials: CS
authors.lastname: Yang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D002288:Adenocarcinoma, Mucinous / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000714:Anastomosis, Surgical / Q000009:adverse effects*; D000818:Animals; D001471:Barrett Esophagus / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003043:Cocarcinogenesis; D018736:DNA Adducts; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D004195:Disease Models, Animal; D004386:Duodenum / Q000601:surgery*; D004847:Epithelial Cells / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004941:Esophagitis / Q000139:chemically induced; D004947:Esophagus / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D005764:Gastroesophageal Reflux / Q000150:complications; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000493:pharmacokinetics / Q000633:toxicity*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D018384:Oxidative Stress; D011183:Postoperative Complications / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
chemical_list: D018736:DNA Adducts; D007527:Isoenzymes; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; D017392:Thiobarbituric Acid Reactive Substances; D000080242:8-Hydroxy-2'-Deoxyguanosine; D008668:Metallothionein; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); D003849:Deoxyguanosine