Hypergastrinemia Promotes Adenoma Progression in the APCMin−/+ Mouse Model of Familial Adenomatous Polyposis
2001
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 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.
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