Hypertrophic gastropathy resembling Ménétrier's disease in transgenic mice overexpressing transforming growth factor alpha in the stomach.

Abstract

Transforming growth factor a (TGFa) is thought to participate in the normal and pathologic processes of numerous tissues, including the gastric mucosa. To explore its role in vivo, transgenic mice were generated overexpressing TGFa in the stomach. TGFa induced dramatic structural and functional lesions of the glandular stomach that were similar to Menetrier's disease in humans. Transgenic mice developed severe adenomatous hyperplasia that resulted in a striking nodular thickening or hypertrophy of the gastric mucosa. Secretions obtained from affected stomachs contained no detectable gastric acid, suggesting that parietal cell function had been greatly impaired. These findings demonstrate that overproduction of TGFa can stimulate cellular proliferation, suppress acid secretion, and perturb organogenesis ofthe stomach oftransgenic mice. Moreover, TGFa may contribute to the pathogenesis of related human hypertrophic gastropathies, such as Menetrier's disease. (J. Clin. Invest. 1992.90:1161-1167

Transgenic overexpression of Reg protein caused gastric cell proliferation and differentiation along parietal cell and chief cell lineages

“…So far, several growth factors have been implicated in the regulation of gastric epithelial cell growth, largely based on studies with cells cultured in vitro (Chen et al, 1991;Rutten et al, 1991Rutten et al, , 1993Yoshiura et al, 1994;Takahashi et al, 1995). Among these growth factors, TGFa is the only one that was shown to exhibit a drastic effect on gastric cell proliferation and differentiation in an in vivo transgenic mouse model Takagi et al, 1992;Sharp et al, 1995). The phenotype of the TGFa-transgenic mouse is the 'opposite' of that of the Reg transgenic mouse presented in this report.…”

“…The phenotype of the TGFa-transgenic mouse is the 'opposite' of that of the Reg transgenic mouse presented in this report. The surface mucous cell population in the gastric gland is greatly expanded, at the expense of chief cells and parietal cells in the TGFa-transgenic mouse Takagi et al, 1992;Sharp et al, 1995). Thus, Reg and TGFa seem to play different parts in the control of differentiation of gastric progenitor cells.…”

The mesenchymal winged helix transcription factor Fkh6 is required for the control of gastrointestinal proliferation and differentiation.

“…Several candidates for such mesenchymal signal mediators have been described (for review, see Traber and Wu 1995), among them transforming growth factor e~ and ~ (TGF~, TGF~I, TGF~2, and TGF~3), neuregulin and scatter factor/hepatocyte growth factor (SF/HGF). Of particular interest was TGFa, as overexpression of this protein in the stomach of transgenic mice led to hypertrophic alterations of the epithelium, some of which are reminiscent of the changes seen in the Fkh6 -lmice (Dempsey et al 1992;Tgaki et al 1992). However, expression of TGFc~ is not altered in Fkh6 mutant mice, as demonstrated by RNase protection analysis (Fig.…”

Cellular markers in the gastric precancerous process

“…Overexpression of TGF-α in transgenic mice leads to the development of a hypertrophic gastropathy resembling Menetrier's disease, but not to frank neoplasia. 116,117 TGF-α immunoreactivity is maintained in intestinal metaplasia and in the intestinal type of gastric cancers but is less commonly expressed in diffuse carcinomas.…”