Evidence for repatterning of the gastric fundic epithelium associated with Menetrier's disease and TGFα overexpression

Background & Aims: Increase of intramucosal transforming growth factor alpha (TGF alpha) levels in the gastric fundus leads to oxyntic atrophy and massive foveolar hyperplasia in both metallothionein (MT)-TGF alpha mice and patients with Menetrier's disease. We have evaluated the hypothesis that increased levels of TGF alpha 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-TGF alpha bigenic mice treated with zinc. The distribution of Pdx1 in MT-TGF alpha mice and Menetrier'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 PdXl(lacZ/+)/MT-TGF alpha 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-TGF alpha mice, 8 weeks of zinc treatment elicited nuclear Pdxl staining throughout the fundic mucosa. TGF alpha treatment in AGS cells led to increases in Pdx1 and gastrin messenger RNA expression. Fundic sections from Menetrier's disease patients showed nuclear Pdx1 staining throughout the fundic glands. Treatment of a Menetrier's disease patient with an anti-epidermal growth factor receptor monoclonal antibody reduced fundic expression of both Pdxl and gastrin. Conclusions: Overexpression of TGF alpha in MT-TGF alpha mice and Menetrier's disease patients elicits ectopic expression in the fundus of PdxJ, consistent with the phenotype of antralization.