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F15. New Clinically Relevant Model of Gastroesophageal Reflux Leading to Barrett’s Metaplasia and Malignant Transformation in Lower Esophagus.
Pramod N Bonde, Carlos Menezes, Zarina Bell, Christine Swarbrick, James Sloan, Sidney Mirvish, Tracy Robson, Stephanie Mckeown, Charles Campbell, James A Mcguigan; Belfast, United Kingdom; Omaha, NE; Coleraine, United Kingdom
Objective:
Gastro-esophageal reflux (GERD) is implicated in esophageal carcinogenesis and consists of predominantly gastric contents in humans. Prior models rely on pure biliary reflux after gastrectomy to induce esophageal cancer but do not develop cancer in the presence of gastric acid. It is not clear if the tumors seen in these models are due to the severe nutritional deficiency or due the biliary reflux. In addition, they fail to show invasiveness or metastases. We report a model of gastroesophageal reflux with mixed gastric and duodenal reflux demonstrating malignant progression and show for the first time that the tumors can metastasize in an animal model.
Methods:
Mixed gastroduodenal reflux was created in the lower esophagus without bypassing the stomach in male Sprague Dawley rats at 10 wk of age. A Half received methyl-n-amyl nitrosamine (MNAN), a dietary mutagen. The experiment was terminated 30 weeks later. Histology was confirmed using PAS, mucicarmine, H &E and alcian blue.
Results:
Eighty two animals completed the study. There were malignant changes noted on the background of Barrett metaplasia progressing to carcinoma in situ with adenocarcinomatous features in the reflux group. The reflux group receiving MNAN, showed shift towards squamous histology (Table I). These changes took place in the presence of gastric secretions. The weight gain over the experimental period was comparable with non-operated controls. Three invasive tumors were identified invading the wall, with one having multiple metastases, including to the lung hila and chest wall (Figure 1).
Conclusions:
We have established a new clinically relevant reflux induced esophageal cancer model. This model mimics human situation with a step wise malignant progression, local invasiveness and potential to metastasize.
Table 1
|
Control (n=20) |
Reflux (n=32) |
Reflux + MNAN (n=30) |
| Barrett metaplasia |
0 |
14 (43.7%) |
12 (40%) |
| Barrett with dysplasia |
0 |
8(25%) |
5(16.6%) |
| Cancers/Carcinoma in situ |
0 |
5(15.6%) |
9(30%) |
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