Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2017; 23(33): 6077-6087
Published online Sep 7, 2017. doi: 10.3748/wjg.v23.i33.6077
High yield reproducible rat model recapitulating human Barrett’s carcinogenesis
Daisuke Matsui, Ashten N Omstead, Juliann E Kosovec, Yoshihiro Komatsu, Emily J Lloyd, Hailey Raphael, Ronan J Kelly, Ali H Zaidi, Blair A Jobe
Daisuke Matsui, Ashten N Omstead, Juliann E Kosovec, Yoshihiro Komatsu, Emily J Lloyd, Hailey Raphael, Ali H Zaidi, Blair A Jobe, Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, PA 15224, United States
Daisuke Matsui, Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Ishikawa 920-1192, Japan
Ronan J Kelly, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD 21231, United States
Author contributions: Matsui D, Omstead AN, and Kosovec JE performed the majority of the experiments, analyzed the data, and wrote the manuscript; Komatsu Y, Lloyd E and Raphael H were instrumental in the model development; Zaidi AH, Kelly RJ, and Jobe BA designed and coordinated the research and wrote the manuscript.
Institutional animal care and use committee statement: This study was conducted with approval from the Institutional Animal Care and Use Committee of Allegheny General Hospital in Pittsburgh, Pennsylvania under Protocol #992.
Conflict-of-interest statement: The authors have no conflicts to report.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Blair A Jobe, MD, Esophageal and Lung Institute, Allegheny Health Network, 4600 North Tower, 4800 Friendship Avenue, Pittsburgh, PA 15224, United States. blair.jobe@ahn.org
Telephone: +1-412-5784026 Fax: +1412-5781434
Received: May 10, 2017
Peer-review started: May 12, 2017
First decision: June 5, 2017
Revised: June 23, 2017
Accepted: July 24, 2017
Article in press: July 24, 2017
Published online: September 7, 2017
Processing time: 120 Days and 5.4 Hours
Abstract
AIM

To efficiently replicate the biology and pathogenesis of human esophageal adenocarcinoma (EAC) using the modified Levrat model of end-to-side esophagojejunostomy.

METHODS

End-to-side esophagojejunostomy was performed on rats to induce gastroduodenoesophageal reflux to develop EAC. Animals were randomly selected and serially euthanized at 10 (n = 6), 17 (n = 8), 24 (n = 9), 31 (n = 6), 38 (n = 6), and 40 (n = 6) wk postoperatively. The esophagi were harvested for downstream histopathology and gene expression. Histological evaluation was completed to determine respective rates of carcinogenic development. Quantitative reverse transcription-polymerase chain reaction was performed to determine gene expression levels of MUC2, CK19, and CK20, and results were compared to determine significant differences throughout disease progression stages.

RESULTS

The overall study mortality was 15%. Causes of mortality included anastomotic leak, gastrointestinal hemorrhage, stomach ulcer perforation, respiratory infection secondary to aspiration, and obstruction due to tumor or late anastomotic stricture. 10 wk following surgery, 100% of animals presented with esophagitis. Barrett’s esophagus (BE) was first observed at 10 wk, and was present in 100% of animals by 17 wk. Dysplasia was confirmed in 87.5% of animals at 17 wk, and increased to 100% by 31 wk. EAC was first observed in 44.4% of animals at 24 wk and increased to 100% by 40 wk. In addition, two animals at 38-40 wk post-surgery had confirmed macro-metastases in the lung/liver and small intestine, respectively. MUC2 gene expression was progressively down-regulated from BE to dysplasia to EAC. Both CK19 and CK20 gene expression significantly increased in a stepwise manner from esophagitis to EAC.

CONCLUSION

Esophagojejunostomy was successfully replicated in rats with low mortality and a high tumor burden, which may facilitate broader adoption to study EAC development, progression, and therapeutics.

Keywords: Esophageal adenocarcinoma; Gastroesophageal reflux disease; Levrat; Esophagojejunostomy; Experimental rat model; Mucin genes; Cytokeratins

Core tip: The current study reportsrefined surgical techniques with improved tumor burdens for the modified Levrat model of end-to-side esophagojejunostomy in a rat for future in vivo studies of esophageal adenocarcinoma (EAC). For the first time, the model was established with significantly reduced mortality and morbidity and further validated through evaluation of conserved EAC disease progression markers, such as mucin and cytokeratins. The reported approach will allow for broader adoption of the model to allow for greater understanding of the complete disease progression spectrum from Barrett’s esophagus to metastatic EAC and aid in the development of novel therapeutics.