Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma.
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 IFNgamma 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 IFNgamma, MKN45 cells were cocultured with IFNgamma or gastrin. IFNgamma 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.
Zavros
Yana
Y
Department of Gastroenterology, University of Michigan, Ann Arbor, MI 48109-0650, USA.
Eaton
Kathryn A
KA
Kang
Weiqun
W
Rathinavelu
Sivaprakash
S
Katukuri
Vinay
V
Kao
John Y
JY
Samuelson
Linda C
LC
Merchant
Juanita L
JL
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002908:Chronic Disease; D017931:DNA Primers; D018450:Disease Progression; D005755:Gastrins / Q000235:genetics / Q000502:physiology*; D005756:Gastritis / Q000473:pathology*; D007150:Immunohistochemistry; D051379:Mice; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*
D017931:DNA Primers; D005755:Gastrins