Evidence for Repatterning of the Gastric Fundic Epithelium Associated With Ménétrier's Disease and TGFα Overexpression

Background & Aims: Increase of intramucosal transforming growth factor α (TGFα) levels in the gastric fundus leads to oxyntic atrophy and massive foveolar hyperplasia in both metallothionein (MT)-TGFα mice and patients with Ménétrier's disease. We have evaluated the hypothesis that increased levels of TGFα 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 Pdx1lacZ/+/MT-TGFα bigenic mice treated with zinc. The distribution of Pdx1 in MT-TGFα 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 Pdx1lacZ/+ 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 Pdx1lacZ/+/MT-TGFα 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-TGFα mice, 8 weeks of zinc treatment elicited nuclear Pdx1 staining throughout the fundic mucosa. TGFα 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 TGFα in MT-TGFα mice and Ménétrier's disease patients elicits ectopic expression in the fundus of Pdx1, consistent with the phenotype of antralization.