Gastroenterology

Gastroenterology

Volume 122, Issue 3, March 2002, Pages 689-696
Gastroenterology

Basic Research
Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic miceā˜†,ā˜†ā˜†

https://doi.org/10.1053/gast.2002.31902Get rights and content

Abstract

Background & Aims: Intestinal-type gastric cancer is often preceded by intestinal metaplasia in humans. The genetic events responsible for the transdifferentiation that occurs in intestinal metaplasia are not well understood. Cdx2, a transcription factor whose expression is normally limited to the intestine, has been detected in gastric intestinal metaplasia. Cdx2 induces differentiation of intestinal epithelial cells in vitro; therefore, we sought to establish whether a causal relationship exists between Cdx2 activation and intestinal metaplasia. Methods: Cdx2 expression was directed to the gastric mucosa in transgenic mice using cis-regulatory elements of Foxa3 (Hnf3Ī³). Transgenic mice were analyzed for histologic and gene expression changes. Results: Histologic examination of the gastric mucosa of the Foxa3/Cdx2 mice revealed the presence of alcian blueā€“positive intestinal-type goblet cells, a hallmark of intestinal metaplasia. In addition, Cdx2 induced the expression of intestine-specific genes. Conclusions: Gastric expression of Cdx2 alone was sufficient to induce intestinal metaplasia in mice. These mice represent a powerful tool to investigate the molecular mechanisms that promote intestinal metaplasia. Moreover, as gastric cancer in humans is often preceded by intestinal metaplasia, the phenotype described here strongly suggests involvement of Cdx2 in the initiation of the process leading to intestinal neoplasia of the gastric mucosa.

GASTROENTEROLOGY 2002;122:689-696

Section snippets

Generation of the Foxa3/Cdx2 yeast artificial chromosome

The Cdx2-expressing transgenic construct was made using a yeast artificial chromosome (YAC) clone containing the complete Foxa3 locus (previously Hnf3Ī³). A ā€œpop-in, pop-outā€ approach was used to introduce the Cdx 2 complementary DNA (cDNA) into a 170-kilobase (kb) Foxa3-YAC (Figure 1).29

. Targeting of a 170-kb YAC spanning the mouse Foxa3 (Hnf3Ī³) gene by insertion of the mouse Cdx2 cDNA. (A) Structure of the unmodified YAC. Restriction sites for NotI (N) are shown. The Foxa3 exons are indicated

The derivation of Cdx2-expressing transgenic animals

Cdx2 expression in the gastric mucosa was achieved through the derivation of transgenic mice in which the mouse Cdx2 cDNA was under the control of the cis-regulatory elements of the winged helix transcription factor Foxa3 in a YAC.29 The Foxa3-YAC had been shown previously to direct copy-numberā€“dependent and integration siteā€“independent expression of a transgene to the glandular gastric mucosa.29 The Cdx2 cDNA was incorporated into the Foxa3 YAC via homologous recombination in yeast as outlined

Discussion

We report that ectopic expression of Cdx2, a homeodomain transcription factor, in the gastric mucosa causes transdifferentiation of the epithelium to an intestinal type, providing the first causal link between Cdx2 expression and intestinal metaplasia. The histologic and molecular changes induced by the expression of Cdx2 in the stomach mimic the changes observed in human intestinal metaplasia, namely the appearance of goblet cells and the activation of intestinal genes in the gastric

Acknowledgements

The authors thank P. G. Traber for his guidance and mentoring, A. K. Rustgi and G. D. Wu for advice and discussions, and S. Mancano for technical assistance.

References (47)

  • J Park et al.

    Intestine-specific activity of the human guanylyl cyclase C promoter is regulated by Cdx2

    Gastroenterology

    (2000)
  • RT Greenlee et al.

    Cancer statistics, 2000

    CA Cancer J Clin

    (2000)
  • AI Neugut et al.

    Epidemiology of gastric cancer

    Semin Oncol

    (1996)
  • P Correa et al.

    Phenotypic and genotypic events in gastric carcinogenesis

    Cancer Res

    (1994)
  • GN Stemmermann

    Intestinal metaplasia of the stomach. A status report

    Cancer

    (1994)
  • M Osborn et al.

    Villin, intestinal brush border hydrolases and keratin polypeptides in intestinal metaplasia and gastric cancer; an immunohistologic study emphasizing the different degrees of intestinal and gastric differentiation in signet ring cell carcinomas

    Virchows Archiv A Pathol Anat Histopathol

    (1988)
  • D Forman

    Helicobacter pylori infection and cancer

    Br Med Bull

    (1998)
  • AJ Tuyns

    Salt and gastrointestinal cancer

    Nutr Cancer

    (1988)
  • K Tajima et al.

    Dietary habits and gastro-intestinal cancers: a comparative case-control study of stomach and large intestinal cancers in Nagoya, Japan

    Jpn J Cancer Res

    (1985)
  • WC You et al.

    Nitrite, N-Nitroso compounds, and other analytes in physiological fluids in relation to precancerous gastric lesions

    Cancer Epidemiol Biomarkers Prev

    (1996)
  • N Matsukura et al.

    Distribution of marker enzymes and mucin in intestinal metaplasia in human stomach and relation of complete and incomplete types of intestinal metaplasia to minute gastric carcinomas

    J Natl Cancer Inst

    (1980)
  • CA Reis et al.

    Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression

    Cancer Res

    (1999)
  • SB Ho et al.

    Mucin gene expression in normal, preneoplastic and neoplastic human gastric epithelium

    Cancer Res

    (1995)
  • Cited by (0)

    ā˜†

    Address requests for reprints to: Debra G. Silberg, M.D., Ph.D., University of Pennsylvania, 415 Curie Boulevard, 650 CRB, Philadelphia, Pennsylvania 19104. e-mail: [email protected]; fax: (215) 573-2024.

    ā˜†ā˜†

    This work was supported by NIH-NIDDK grants K08-DK02375, R03-DK56082, and R01-DK69539 (to D.G.S.), R01-DK53839 (to K.H.K.), and the Morphology, Molecular Biology and Transgenic Cores of the Center for Molecular Studies in Digestive Disease at the University of Pennsylvania (P30-DK50306).

    View full text