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Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma

Oncogene volume 24, pages 2354–2366 (2005)Cite this article

Abstract

The current study tests the hypothesis that chronic atrophic gastritis from hypochlorhydria in the gastrin-deficient mouse predisposes the stomach to gastric cancer. Gross morphology and histology of 12-month-old wild-type (WT), gastrin-deficient (G−/−) and somatostatin-deficient (SOM−/−) mice were examined. Parietal and G cells, Ki67, TUNEL, villin and MUC2 expression were analysed by immunohistochemistry. RUNX3 and STAT3 expression was analysed by Western blot. Anchorage-independent growth was determined by cell cluster formation in soft agar. Compared to the WT and SOM−/− mice, hypochlorhydric G−/− mice developed parietal cell atrophy, significant antral inflammation and intestinal metaplasia. Areas of metaplasia within the G−/− mouse stomach showed decreased RUNX3 expression with elevated MUC2 and villin expression. Cells isolated from the tumor grew in soft agar. However, the cells isolated from WT, nontransformed G−/− and SOM−/− gastric tissue did not form colonies in soft agar. Consistent with elevated antral proliferation, tumor tissue isolated from the G−/− mice showed elevated phosphorylated STAT3 expression. We then examined the mechanism by which STAT3 was constitutively expressed in the tumor tissue of the G−/− mice. We found that IFNγ expression was also significantly higher in the tumor tissue of G−/− mice compared to WT and SOM−/− animals. To determine whether STAT3 was regulated by IFNγ, MKN45 cells were cocultured with IFNγ or gastrin. IFNγ significantly stimulated phosphorylation of STAT3 in the MKN45 cell line, but not gastrin. Therefore, we show here that in the hypochlorhydric mouse stomach, the chronic gastritis, atrophy, metaplasia, dysplasia paradigm can be recapitulated in mice. Moreover, neoplastic transformation of the antral gastric mucosa does not require gastrin.

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Abbreviations

WT:

wild-type mice

G−/−:

gastrin-deficient mice

SOM−/−:

somatostatin-deficient

G cells:

gastrin-expressing cells

H&E:

hematoxylin and eosin

G−/−M:

metaplastic tissue in gastrin-deficient mice

G−/−T:

tumor tissue in gastrin-deficient mice

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Acknowledgements

This work was supported in part by Public Health Service Grants DK45729, DK61410 and DK62041 (JLM) and Michigan Gastrointestinal Peptide Research Center Pilot Feasibility Grant DK34933 (YZ). Rabbit gastrin antisera number 1296 was from the Center for Ulcer Research and Education Digestive Disease Research Center/RIA Core (University of California, Los Angeles) (Grant DK41301). RIAs were performed in the University of Michigan Gastrointestinal Peptide Research Center (DK34933). We also acknowledge the valuable assistance of Judy Poore for PAS/alcian blue staining, Kathy McClinchey (McClinchey Histology Lab, Inc., Stockbridge, MI, USA) for paraffin embedding and sectioning tissue.

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Authors and Affiliations

  1. Department of Gastroenterology, University of Michigan, Ann Arbor, MI, USA

    Yana Zavros, Weiqun Kang, Sivaprakash Rathinavelu, Vinay Katukuri, John Y Kao & Juanita L Merchant

  2. Unit for Laboratory Medicine, University of Michigan, Ann Arbor, MI, USA

    Kathryn A Eaton

  3. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Linda C Samuelson & Juanita L Merchant

  4. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA

    Juanita L Merchant

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  1. Yana Zavros
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Correspondence to Juanita L Merchant.

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Zavros, Y., Eaton, K., Kang, W. et al. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma. Oncogene 24, 2354–2366 (2005). https://doi.org/10.1038/sj.onc.1208407

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