Loss of function of Trp53, but not Apc, leads to the development of esophageal adenocarcinoma in mice with jejunoesophageal reflux.
BACKGROUND
APC and TP53 are tumor suppressor genes known to be altered frequently in human esophageal adenocarcinoma (EAC), which arises as a complication of reflux disease. To determine the functional role of these genes in the development of EAC, we have created reflux in mice gene-targeted for either Trp53 or Apc.


METHODS
Wild-type (WT), p53-knockout (Trp53-/-), or Apc-mutated (ApcMin/+) mice were generated in our breeding colony. Total gastrectomy with esophagojejunostomy was performed at 6 weeks of age, creating jejunoesophageal reflux. Unoperated control mice were maintained under identical conditions. Mice were sacrificed at 30 weeks of age. Histology of the esophagus and jejunal anastamosis or gastroesophageal junction was reviewed by a single pathologist blinded to the genotype of the animal.


RESULTS
The esophagus was normal in all of the unoperated mice (6 ApcMin/+, 6 WT, and 6 Trp53-/-). All operated mice (6 ApcMin/+, 12 WT, and 4 Trp53-/-) had esophagitis, with squamous hyperplasia and early focal ulceration. Barrett's metaplasia was identified in 33% of the operated ApcMin/+ (2/6) and 25% of the Trp53-/- (1/4) mice, but not in the WT mice. Of 4 operated Trp53-/- mice, all developed severe dysplasia of the squamous epithelium and 2 (50%) had EAC on histology, although no gross tumors were seen. No severe dysplasia or carcinoma was identified in any of the ApcMin/+ or WT mice.


CONCLUSIONS
Loss of either Trp53 or Apc leads to the development of columnar metaplasia, whereas loss of Trp53, but not Apc, leads to development of cancer in mice with jejunoesophageal reflux.
Fein
M
M
Department of Surgery, University of Southern California, Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, California 90033-4612, USA.
Peters
J H
JH
Baril
N
N
McGarvey
M
M
Chandrasoma
P
P
Shibata
D
D
Laird
P W
PW
Skinner
K A
KA
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D001471:Barrett Esophagus / Q000235:genetics / Q000473:pathology; D004848:Epithelium / Q000473:pathology; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D004947:Esophagus / Q000473:pathology; D005764:Gastroesophageal Reflux / Q000235:genetics* / Q000473:pathology; D017491:Genes, APC / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics*; D007579:Jejunal Diseases / Q000235:genetics* / Q000473:pathology; D007580:Jejunal Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation