Gastroenterology

Gastroenterology

Volume 136, Issue 4, April 2009, Pages 1288-1296
Gastroenterology

Basic—Alimentary Tract
Amphiregulin-Deficient Mice Develop Spasmolytic Polypeptide Expressing Metaplasia and Intestinal Metaplasia

https://doi.org/10.1053/j.gastro.2008.12.037Get rights and content

Background & Aims

The loss of parietal cells from the fundic mucosa leads to the emergence of metaplastic lineages associated with an increased susceptibility to neoplastic transformation. Both intestinal metaplasia (IM) and spasmolytic polypeptide (TFF2/SP) expressing metaplasia (SPEM) have been identified in human stomach, but only SPEM is present in most mouse models of gastric metaplasia. We previously determined that loss of amphiregulin (AR) promotes SPEM induced by acute oxyntic atrophy. We have now examined whether SPEM in the AR−/− mouse predisposes the stomach to gastric neoplasia.

Methods

Gross pathology of 18-month-old wild-type, AR−/−, and TGF-α−/− mice were examined. Ki-67, β-catenin, Pdx-1, TFF3, and TFF2/SP expression was analyzed by immunohistochemistry. Metaplastic gastric mucosa was analyzed by dual immunostaining for TFF2/SP with MUC2 or TFF3.

Results

By 18 months of age, more than 70% of AR−/− mice developed SPEM while 42% showed goblet cell IM labeled with MUC2, TFF3, and Pdx-1. A total of 28% had invasive gastric lesions in the fundus. No antral abnormalities were observed in AR−/− mice. Metaplastic cell lineages in AR−/− mice showed increases in cell proliferation and cytosolic β-catenin expression. Dual staining for TFF2/SP with MUC2 or TFF3 showed glands containing both SPEM and IM with intervening cells expressing both TFF2/SP and MUC2 or TFF2/SP and TFF3.

Conclusions

AR−/− mice develop SPEM, which gives rise to goblet cell IM and invasive fundic dysplastic lesions. The AR−/− mouse represents the first mouse model for spontaneous development of fundic SPEM with progression to IM.

Section snippets

Animals

The generation of AR-null mice, heterozygous AR+/− mice, and TGF-α–null mice has been described previously in detail.22 Mice were maintained on the C57BL/6 background under specific pathogen-free conditions in individual, sterile microisolator cages in nonbarrier mouse rooms. C57BL/6 mice were obtained from Jackson Laboratories (Bar Harbor, ME). During the experiments, the mice were maintained with regular mouse chow and water ad libitum in a temperature-controlled room under a 12-hour

Spontaneous Tumors Develop in the Gastric Fundus, But Not in the Antrum, of AR−/− Mice

We recently found that AR deficiency caused more extensive induction of SPEM in response to acute oxyntic atrophy, suggesting differential roles of respective EGF ligand in cell lineage differentiation in the gastric unit.22 To evaluate the long-term effects of AR deficiency, we systemically evaluated the stomachs of AR−/− mice at 10 and 18 months of age compared with age-matched WT mice. To examine the long-term effects of other EGR ligands produced by parietal cells, TGF-α–deficient mice were

Discussion

Gastric adenocarcinoma can be categorized by 2 histologic characteristics. The diffuse type is remarkable for its poorly differentiated phenotype in which the glandular architecture is completely lost. Recent investigations in cohorts of familial diffuse gastric cancer as well as in some patients with sporadic diffuse cancer have shown a causal association of carcinogenesis with mutations in cadherins and catenins.27, 28, 29 Mutations in E-cadherin or β-catenin lead to a loss of polarity and

Acknowledgments

The authors thank Drs Adam Smolka, Nicholas Wright, Christopher Wright, Daniel Podolsky, and David Alpers for the gifts of antibodies.

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by a Department of Veterans Affairs Merit Review Award (to J.R.G.); a pilot project grant from the Vanderbilt Specialized Program of Research Excellence in Gastrointestinal Cancer (P50 CA95103 to J.R.G.); the American Gastroenterological Association Funderburg Award in Gastric Biology Related to Cancer (to J.R.G.); a Discovery Grant from the Vanderbilt-Ingram Cancer Center and National Institutes of Health grant DK071590 (to J.R.G.); National Institutes of Health grants DK73902, DK58587, and DK77955 (to R.M.P.); and a grant from the Vanderbilt Digestive Diseases Research Center (DK058404 to R.M.P.).

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