Deletion of functional gastrin gene markedly increases colon carcinogenesis in response to azoxymethane in mice

Stephanie Cobb, Thomas Wood, Lino Tessarollo, Marco Velasco, Randall Given, Andrea Varro, Nadya Tarasova, Pomila Singh

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Background & Aims: We recently reported that transgenic mice overexpressing progastrin were at a higher risk for developing colon cancers in response to azoxymethane (AOM), whereas mice overexpressing gastrin-17 were at a reduced risk. To examine further the role of gastrins in colon carcinogenesis, we generated gastrin gene knockout mice (GAS-KO). Methods: The height and proliferative index (PI) of colonic crypts were similar in GAS-KO and wild-type (WT) mice, suggesting that the absence of gastrins in GAS-KO mice did not significantly affect the growth of colonic mucosa. GAS-KO and WT mice were treated with AOM for 3-4 weeks; control mice received saline. Results: Colonic proliferation in response to AOM was significantly increased in GAS-KO vs. WT mice. Aberrant crypt foci (ACFs) were similarly increased significantly by ∼2-5fold in GAS-KO vs. WT mice after 2 weeks of AOM treatment. Female GAS-KO mice developed adenomas (Ads) and adenocarcinomas (AdCAs) at earlier times (∼10 months) than the male GAS-KO mice and the male and female WT mice (∼12 months). The total numbers of Ads and AdCAs were significantly higher in GAS-KO than in WT mice. Conclusions: These results suggest the novel possibility that loss of gastrin expression (and hence amidated gastrins) significantly increases susceptibility to colon carcinogenesis in response to AOM. Previous studies with FVB/N transgenic mice similarly suggested a protective role of amidated gastrins against colon carcinogenesis, which supports the present findings of an increase in colon carcinogenesis in GAS-KO mice lacking normal physiological levels of amidated gastrins.

Original languageEnglish (US)
Pages (from-to)516-530
Number of pages15
JournalGastroenterology
Volume123
Issue number2
DOIs
StatePublished - Aug 2002

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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