Hypergastrinemia promotes adenoma progression in the APC(Min-/+) mouse model of familial adenomatous polyposis.
Serum hypergastrinemia promotes the growth of colorectal adenocarcinoma. Some colorectal adenomas express cholecystokinin B/gastrin receptor mRNA, and thus hypergastrinemia may increase progression through the adenoma-carcinoma sequence. This was investigated in the multiple intestinal neoplasia APC(Min-/+) mouse. Serum gastrin levels in APC(Min-/+) mice were elevated 5-6-fold by oral administration of omeprazole (75 mg/kg). Terminal tumor burden was monitored by onset of anemia. A labeling index was generated by immunohistochemical detection of bromodeoxyuridine incorporation. Serum gastrin was neutralized by antigastrin antibodies raised in situ by use of a gastrin immunogen, Gastrimmune. Hypergastrinemia resulted in reduced survival of the APC(Min-/+) mice from a median survival of 13 weeks in the controls to 10 weeks following omeprazole treatment (P < 0.00001, log-rank test). The labeling indices of adenomas from the small and large intestines of omeprazole-treated mice were increased 35 and 29%, respectively (P < 0.05 and P < 0.025, respectively). Gastrimmune immunization reversed both the survival effect and the increased proliferation resulting from serum hypergastrinemia. Hypergastrinemia may promote the progression of existing premalignant colonic lesions by increasing proliferation. Clinical investigations should determine whether this occurs in the human scenario, considering the widespread use of proton pump inhibitors.
Watson
S A
SA
Department of Surgery, University of Nottingham, United Kingdom. sue.watson@nottingham.ac.uk
Smith
A M
AM
D000236:Adenoma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D025601:Adenomatous Polyposis Coli Protein; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D019496:Cancer Vaccines; D015179:Colorectal Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004168:Diphtheria Toxoid / Q000008:administration & dosage; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005755:Gastrins / Q000008:administration & dosage / Q000097:blood* / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006579:Heterozygote; D007114:Immunization; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009853:Omeprazole / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000235:genetics; D015996:Survival Rate
D025601:Adenomatous Polyposis Coli Protein; D019496:Cancer Vaccines; D003598:Cytoskeletal Proteins; D004168:Diphtheria Toxoid; D005755:Gastrins; D012333:RNA, Messenger; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C482698:gastrin immunogen; D001973:Bromodeoxyuridine; D009853:Omeprazole