Deletion of functional gastrin gene markedly increases colon carcinogenesis in response to azoxymethane in mice.
OBJECTIVE
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 approximately 2-5-fold 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 ( approximately 10 months) than the male GAS-KO mice and the male and female WT mice ( approximately 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.
Cobb
Stephanie
S
Department of Anatomy and Neurosciences, University of Texas Medical Branch, Galveston, Texas 77555-1043, USA.
Wood
Thomas
T
Tessarollo
Lino
L
Velasco
Marco
M
Given
Randall
R
Varro
Andrea
A
Tarasova
Nadya
N
Singh
Pomila
P
D000818:Animals; D001397:Azoxymethane; D003110:Colonic Neoplasms / Q000209:etiology* / Q000473:pathology; D005260:Female; D005755:Gastrins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011230:Precancerous Conditions / Q000209:etiology / Q000473:pathology
D005755:Gastrins; D001397:Azoxymethane