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J Thorac Cardiovasc Surg 2007;133:763-769
© 2007 The American Association for Thoracic Surgery

General Thoracic Surgery

Cytogenetic characterization and gene expression profiling in the rat reflux-induced esophageal tumor model

Pramod Bonde, MD, MS, FRCSa,1, Guoping Sui, MDb,2, Surajit Dhara, PhDb, Jiaai Wang, BSc, Apoorv Broor, MDc, Irene F. Kim, PhDd, John E. Wiley, PhDe, Guy Marti, MDc, Mark Duncan, MDc, Elizabeth Jaffee, MDf, Elizabeth Montgomery, MDb, Anirban Maitra, MBBSb,f,3, John W. Harmon, MDc,*

a Department of Cardiothoracic Surgery, Johns Hopkins University School of Medicine, Baltimore, Md
b Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Md
d Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
f Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Md
c Department of Surgery, Johns Hopkins Bayview Medical Center, Baltimore, Md
e Department of Pediatrics, Brody School of Medicine, East Carolina University, Greenville, NC.

Received for publication January 31, 2006; revisions received July 11, 2006; accepted for publication July 17, 2006.

* Address for reprints: John Harmon, MD, Johns Hopkins Bayview Medical Center, Room 5C, Bldg A, 4940 Eastern Ave, Baltimore, MD 21224. (Email: jharmon{at}jhmi.edu).

Objectives: The reasons for the increasing incidence of esophageal adenocarcinoma are not clear. A causal relation between gastroesophageal reflux disease and esophageal adenocarcinoma has been suggested. Support for this comes from the development of esophageal adenocarcinoma in the rat reflux model. However, to date, no systematic characterization of the tumors derived from this model has been reported.

Methods: We induced biliary reflux by creating esophagojejunal anastomoses in 12 Sprague–Dawley rats. The experiment was terminated at 9 months, and rat esophagi were harvested for histopathologic documentation of reflux-associated changes and evidence of tumor formation. Three cell lines were established from 2 of the reflux-associated tumors. We tested the ability of these cells to grow in vitro in tissue culture and in vivo as xenografts in an orthotopic location at the gastroesophageal junction. Furthermore, we performed a cytogenetic analysis and determined the array-based gene expression profiles of these 3 rodent carcinoma lines compared with normal esophageal mucosa.

Results: At 9 months, 12 of 12 rodents had histologic features of metaplastic columnar epithelium in the esophagus, with 7 having invasive carcinomas with glandular differentiation (either adenocarcinomas or adenosquamous carcinomas). The 3 cell lines established from 2 reflux-associated tumors were capable of sustained in vitro propagation and grew successfully as xenografts in both subcutaneous and orthotopic locations, confirming the tumorigenic nature of these lines. Despite their establishment from primary tumors with glandular features, the histology of the xenografts was that of well-differentiated squamous carcinomas. Karyotype analyses demonstrated cytogenetic heterogeneity and aneuploidy; furthermore, translocation (7:11) was present in all 3 lines. Array-based gene expression profiling confirmed upregulation of several cancer-related genes important in human esophageal cancer. Quantitative reverse transcription–polymerase chain reaction was used to confirm the differential expression of selected transcripts (vascular endothelial growth factor [VEGF], polo-like kinases [PLK], cyclin dependent kinase 4 [CDK4], hypoxia-inducible factor 1{alpha} [HIF1{alpha}], and insulin-like growth factor 1 [IGF-1]) in comparison with nonneoplastic esophageal mucosal scrapings.

Conclusions: The rodent reflux model is capable of inducing metaplastic epithelial changes simulating Barrett esophagus, as well as subsequent neoplastic transformation, at a high frequency. Cell lines have been established from these tumors that are capable of in vitro and in vivo passaging. The rodent reflux model should be a valuable model for studying therapy and chemoprevention efforts for Barrett esophagus, whereas the established cell lines provide a useful resource for drug discovery and other high-throughput studies.

Abbreviations and Acronyms CDK-4 = cyclin dependent kinase 4; HIF1{alpha} = hypoxia-inducible factor 1{alpha}; IGF-1 = insulin-like growth factor; PLK = polo-like kinases; RT-PCR = reverse transcription–polymerase chain reaction; VEGF = vascular endothelial growth factor






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