Gastric achlorhydria in H/K-ATPase-deficient (Atp4a(-/-)) mice causes severe hyperplasia, mucocystic metaplasia and upregulation of growth factors.
BACKGROUND
Gastric neoplasia is common in humans, yet controversy remains over contributions of chronic achlorhydria, gastrinemia and hyperplasia, to cancer risk. To study this, mice lacking the gastric H/K-ATPase (Atp4a(-/-) mice) were used to determine whether chronic loss of acid secretion, with attendant hypergastrinemia, predisposes to cancer phenotype.


METHODS
Atp4a(-/-) and Atp4a(+/+) mice, paired for age and gender, were examined at 3, 8, 12 and 20 months for histopathology, and for expression of the trefoil factor family (TFF)1-3, Reg IIIbeta, gamma and delta, osteopontin, CD44, chromogranin A, Crp-ductin, and galectin, all of which are important in cell growth.


RESULTS
By 8 months, the glandular stomach of the Atp4a(-/-) mice doubled in weight and thickness, and several modulators of growth were increased. Female Atp4a(-/-) mice were more hyperplastic than Atp4a(-/-) males at 12 and 20 months. By 1 year, severe mucocystic hyperplasia, incomplete intestinal metaplasia, ciliated metaplasia, a shift in mucins from neutral to acidic, and inflammation were widespread. Cells in the mucus pit zone developed a pyloric-type appearance, containing large hyaline-like, periodic acid-Schiff (PAS)-negative/alcian blue-negative inclusions. But critical characteristics of gastric neoplasia, such as nuclear atypia, invasion into the muscularis mucosa, and metastases were absent. In Atp4a(-/-) mice, chromogranin A and histidine decarboxylase, RegIIIgamma and delta, TFF3, osteopontin and CD44 were upregulated while Reg IIIbeta, and TFF1 were reduced.


CONCLUSIONS
Chronic achlorhydria and hypergastrinemia in aged Atp4a(-/-) mice produced progressive hyperplasia, mucocystic and incomplete intestinal metaplasia, and the upregulation of growth factors without histological evidence of neoplasia.
Judd
Louise M
LM
Department of Medicine, University of Melbourne, Western Hospital, Melbourne, Victoria, Australia.
Andringa
Anastasia
A
Rubio
Carlos A
CA
Spicer
Zachary
Z
Shull
Gary E
GE
Miller
Marian L
ML
D000126:Achlorhydria / Q000378:metabolism* / Q000473:pathology; D000367:Age Factors; D000818:Animals; D004195:Disease Models, Animal; D004714:Endometrial Hyperplasia / Q000473:pathology; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D017506:H(+)-K(+)-Exchanging ATPase / Q000172:deficiency* / Q000235:genetics; D006965:Hyperplasia; D008297:Male; D008679:Metaplasia; D051379:Mice; D018345:Mice, Knockout; D012737:Sex Factors; D013270:Stomach / Q000473:pathology
D017506:H(+)-K(+)-Exchanging ATPase