title: Gastric achlorhydria in H/K-ATPase-deficient (Atp4a(-/-)) mice causes severe hyperplasia, mucocystic metaplasia and upregulation of growth factors.
abstract: 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.
authors.affiliation: Department of Medicine, University of Melbourne, Western Hospital, Melbourne, Victoria, Australia.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Judd
authors.forename: Anastasia
authors.initials: A
authors.lastname: Andringa
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rubio
authors.forename: Zachary
authors.initials: Z
authors.lastname: Spicer
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.forename: Marian L
authors.initials: ML
authors.lastname: Miller
mesh_terms: 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
chemical_list: D017506:H(+)-K(+)-Exchanging ATPase