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[Cancer Research 61, 625-631, January 15, 2001]
© 2001 American Association for Cancer ResearchCarcinogenesis |
Hypergastrinemia Promotes Adenoma Progression in the APCMin-/+ Mouse Model of Familial Adenomatous Polyposis1
Sue A. Watson2 and Andrew M. Smith
Academic Unit of Cancer Studies, Department of Surgery, University of Nottingham, Nottingham NG7 2UH, United Kingdom

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ABSTRACT
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 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 APCMin-/+ mouse. Serum gastrin levels in APCMin-/+ mice were elevated 5–6-fold by oral administration ofomeprazole (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 APCMin-/+ mice from a median survival of 13 weeks inthe 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.

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ABSTRACT
INTRODUCTION
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Gastrin has beendescribed as a growth factor for colorectal malignancy for well over a decade, and it is known to mediate proliferation via both endocrine and autocrine/paracrine mechanisms (1, 2, 3) .
Elevated serum gastrin levels can be a feature of a number of clinical conditions, including ZES3 (4, 5, 6, 7) and PA (8) , but possibly more importantly as a result of infection with Helicobacter pylori (9 , 10) andafter the administration of proton pump inhibitors (11 , 12) .
In humans, increased proliferation of colonic crypts has been confirmed in patients with PA and ZES (13) . However, the majority of epidemiological studies performed to date in patients with sustained hypergastrinemia have failed to show an enhanced risk of colorectal cancer. In patients with PA, although conflicting studies have...