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Alterations in Manganese Superoxide Dismutase Expression in the Progression From Reflux Esophagitis to Esophageal Adenocarcinoma

¹ Division of Surgical Oncology, University of Louisville School of Medicine, 315 E Broadway #312, Louisville, Kentucky 40202
² Division of Gastroenterology/Hepatology, University of Louisville School of Medicine, 315 E Broadway #312, Louisville, Kentucky 40202
³ Department of Anatomical Pathology, University of Louisville School of Medicine, 315 E Broadway #312, Louisville, Kentucky 40202

Correspondence: Address correspondence and reprint requests to: Robert C. G. Martin, MD; E-mail: robert.martin{at}louisville.edu

Background: Comprehensive understanding of the basic mechanisms in the progression of esophagitis, Barrett esophagus (BE), and esophageal adenocarcinoma (EAC) is urgently needed to develop a management strategy for an effective screening of BE and management of EAC. The aim of this study is to provide a detailed insight of the histology and the cellular and molecular events associated with the genesis of BE and EAC under the esophagoduodenal reflux conditions.

Methods: Esophagoduodenal anastomosis (EDA) was performed on rats. Animals were weighed weekly and killed after 1, 2, 3, 4, 5, and 6 months. The entire esophagi were examined for macroscopic and microscopic changes and for manganese superoxide dismutase (MnSOD) expression, and TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assay was performed.

Results: Morphological transformation from esophagitis (100% of animals) to BE (66% of animals) to EAC was observed after 3 months. There was marked loss of MnSOD expression in animals with esophagitis and BE at 1 and 2 months, with an increase in expression during the transformation to dysplasia and EAC. Increased proliferation and apoptosis was observed and reached a peak at months 1 and 2. Greatly increased levels of 8-hydroxy-deoxyguanosine was found during the progression to EAC.

Conclusions: The morphological transformation of the esophageal mucosa is an adaptive process, and it is an important foundation for the transdifferentiation of BE and cancer. The significant loss of MnSOD expression to achieve BE and then the adaptive increase in expression to achieve dysplasia and EAC during this transformation may represent a predictive marker in identifying patients who will progress from BE to EAC.

Key Words: Superoxide dismutase • Barrett esophagus • Esophageal adenocarcinoma

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