Evidence for repatterning of the gastric fundic epithelium associated with Ménétrier's disease and TGFalpha overexpression.
OBJECTIVE
Increase of intramucosal transforming growth factor alpha (TGFalpha) levels in the gastric fundus leads to oxyntic atrophy and massive foveolar hyperplasia in both metallothionein (MT)-TGFalpha mice and patients with Ménétrier's disease. We have evaluated the hypothesis that increased levels of TGFalpha in the fundus induces an antral pattern of cell differentiation in fundic glands by studying Pdx1, a transcription factor whose expression normally is confined to the gastric antrum.


METHODS
Induction of Pdx1 expression was evaluated in Pdx1(lacZ/+)/MT-TGFalpha bigenic mice treated with zinc. The distribution of Pdx1 in MT-TGFalpha mice and Ménétrier's disease patients was evaluated with anti-Pdx1 antibodies. Transcript levels were evaluated by quantitative polymerase chain reaction in mouse and human tissues and AGS cells.


RESULTS
In Pdx1(lacZ/+) mice, Pdx1 was expressed in antral mucosal cells including gastrin cells and TFF2-expressing deep glandular mucous cells. Zinc treatment for 2 to 8 weeks in Pdx1(lacZ/+)/MT-TGFalpha transgenic mice resulted in expression of Pdx1 throughout the fundus. No ectopic fundic Pdx1 expression was observed in either H. felis-infected or DMP777-treated mice. In MT-TGFalpha mice, 8 weeks of zinc treatment elicited nuclear Pdx1 staining throughout the fundic mucosa. TGFalpha treatment in AGS cells led to increases in Pdx1 and gastrin messenger RNA expression. Fundic sections from Ménétrier's disease patients showed nuclear Pdx1 staining throughout the fundic glands. Treatment of a Ménétrier's disease patient with an anti-epidermal growth factor receptor monoclonal antibody reduced fundic expression of both Pdx1 and gastrin.


CONCLUSIONS
Overexpression of TGFalpha in MT-TGFalpha mice and Ménétrier's disease patients elicits ectopic expression in the fundus of Pdx1, consistent with the phenotype of antralization.
Nomura
Sachiyo
S
Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2733, USA.
Settle
Stephen H
SH
Leys
Charles M
CM
Means
Anna L
AL
Peek
Richard M
RM
Leach
Steven D
SD
Wright
Christopher V
CV
Coffey
Robert J
RJ
Goldenring
James R
JR
D000818:Animals; D001284:Atrophy; D004848:Epithelium / Q000473:pathology; D005748:Gastric Fundus / Q000473:pathology*; D005755:Gastrins / Q000235:genetics; D005758:Gastritis, Hypertrophic / Q000473:pathology* / Q000503:physiopathology*; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics; D006965:Hyperplasia; D051379:Mice; D008822:Mice, Transgenic; D009077:Mucins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D010295:Parietal Cells, Gastric / Q000473:pathology; D010455:Peptides / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D000071164:Trefoil Factor-2
D005755:Gastrins; D018398:Homeodomain Proteins; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; C000604007:TFF2 protein, human; C481546:TFF2 protein, mouse; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; D000071164:Trefoil Factor-2; C084010:pancreatic and duodenal homeobox 1 protein