Gastroesophageal reflux leads to esophageal cancer in a surgical model with mice.
BACKGROUND
Esophago-gastroduodenal anastomosis with rats mimics the development of human Barrett's esophagus and esophageal adenocarcinoma by introducing mixed reflux of gastric and duodenal contents into the esophagus. However, use of this rat model for mechanistic and chemopreventive studies is limited due to lack of genetically modified rat strains. Therefore, a mouse model of esophageal adenocarcinoma is needed.


METHODS
We performed reflux surgery on wild-type, p53A135V transgenic, and INK4a/Arf+/- mice of A/J strain. Some mice were also treated with omeprazole (1,400 ppm in diet), iron (50 mg/kg/m, i.p.), or gastrectomy plus iron. Mouse esophagi were harvested at 20, 40 or 80 weeks after surgery for histopathological analysis.


RESULTS
At week 20, we observed metaplasia in wild-type mice (5%, 1/20) and p53A135V mice (5.3%, 1/19). At week 40, metaplasia was found in wild-type mice (16.2%, 6/37), p53A135V mice (4.8%, 2/42), and wild-type mice also receiving gastrectomy and iron (6.7%, 1/15). Esophageal squamous cell carcinoma developed in INK4a/Arf+/- mice (7.1%, 1/14), and wild-type mice receiving gastrectomy and iron (21.4%, 3/14). Among 13 wild-type mice which were given iron from week 40 to 80, twelve (92.3%) developed squamous cell carcinoma at week 80. None of these mice developed esophageal adenocarcinoma.


CONCLUSIONS
Surgically induced gastroesophageal reflux produced esophageal squamous cell carcinoma, but not esophageal adenocarcinoma, in mice. Dominant negative p53 mutation, heterozygous loss of INK4a/Arf, antacid treatment, iron supplementation, or gastrectomy failed to promote esophageal adenocarcinoma in these mice. Further studies are needed in order to develop a mouse model of esophageal adenocarcinoma.
Hao
Jing
J
Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. haoj2@mail.nih.gov
Liu
Ba
B
Yang
Chung S
CS
Chen
Xiaoxin
X
D000230:Adenocarcinoma / Q000209:etiology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000209:etiology* / Q000473:pathology; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D005260:Female; D005743:Gastrectomy / Q000009:adverse effects*; D005764:Gastroesophageal Reflux / Q000150:complications* / Q000209:etiology*; D007501:Iron / Q000009:adverse effects; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009853:Omeprazole / Q000009:adverse effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000897:Anti-Ulcer Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53; D007501:Iron; D009853:Omeprazole