Induction of inflammatory bowel disease accelerates adenoma formation in Min +/- mice.
BACKGROUND
The accelerated incidence of colorectal carcinoma in individuals with inflammatory bowel disease suggests that cellular perturbation triggered by chronic inflammation is linked to the development of dysplasia and neoplastic transformation. To test the mechanistic links between these processes, we employed the following murine strains: (1) multiple intestinal neoplasia (Min) +/- mice, bearing a mutation in the adenomatous polyposis coli (APC) gene; (2) mice deficient in interleukin 10 (IL-10), which normally develop enterocolitis; and (3) Min +/-/IL-10 null mice, first developed in our laboratory.


METHODS
Mice with either parental strain or the cross were sacrificed at time points ranging from 10 to 30 weeks of age. The small bowel and colon of 170 IL-10 null mice, 31 Min +/- mice, and 120 Min +/-/IL-10 null mice were examined microscopically.


RESULTS
The number of flat adenomas was increased in the colons of the Min +/-/IL-10-/- mice, compared with the Min +/- mice (P = .0005). Neither colitis-type dysplasia nor carcinoma was increased in the Min +/-/IL-10 -/-, compared with the IL-10 null mice (P = .18). Mice deficient in IL-10 developed colitic-type dysplasia (P = .0001) or carcinoma (P = .0001) correlated with increasing inflammation.


CONCLUSIONS
Breeding the Min +/- genotype into the IL-10 -/- background increased the incidence of colonic adenomas. Our studies demonstrate that acceleration of dysplasia and progression to invasion were associated with the degree of the inflammatory response in mice deficient in IL-10. These findings provide a novel system to dissect the pathways by which inflammatory mechanisms accelerate adenoma formation.
Huang
Emina H
EH
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. eminah@umich.edu
Park
Juliet C
JC
Appelman
Henry
H
Weinberg
Alan D
AD
Banerjee
Mousumi
M
Logsdon
Craig D
CD
Schmidt
Ann Marie
AM
D000236:Adenoma / Q000209:etiology*; D000818:Animals; D003110:Colonic Neoplasms / Q000209:etiology*; D017491:Genes, APC / Q000502:physiology*; D005838:Genotype; D015212:Inflammatory Bowel Diseases / Q000150:complications*; D016753:Interleukin-10 / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D016753:Interleukin-10