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Helicobacter hepaticus infection promotes colon tumorigenesis in the BALB/c-Rag2(-/-) Apc(Min/+) mouse

Claude M Nagamine et al. Infect Immun. 2008 Jun.

Abstract

Adenomatous polyposis coli (APC) mutations are linked to human and mouse colorectal cancers. The Apc multiple intestinal neoplasia (Min) mouse mutation causes adenomas to develop throughout the small and large intestines. The BALB-Min (C.B6-Apc(Min/+)) congenic strain was generated by backcrossing into BALB/c the Apc(Min) allele from C57BL/6J-Apc(Min/+) mice. BALB-Min mice have a low tumor multiplicity (27.4 small intestine tumors/mouse) and a relatively long life span (>1 year) that makes them amenable to long-term studies. To investigate the interplay of the adaptive immune system and intestinal tumorigenesis, the immunodeficient compound mutant strain BALB-RagMin (C.Cg-Rag2(-/-) Apc(Min/+)) was generated. BALB-RagMin mice had a significant increase in tumors in the small, but not large, intestine relative to their BALB-Min counterparts (43.0 versus 24.0 tumors/mouse, respectively). The results suggest that the adaptive immune system plays a role in either the elimination or the equilibrium phase of cancer immunoediting in the small intestine in this model. We investigated the effect of the enterohepatic bacterial pathogen Helicobacter hepaticus on liver and intestine tumorigenesis in BALB-RagMin mice. H. hepaticus-infected BALB-RagMin mice developed moderate hepatitis, moderate typhlitis, and mild colitis. There were no differences in small intestine and cecal tumor multiplicity, regionality, or size relative to that in uninfected mice. However, H. hepaticus-infected BALB-RagMin mice had a significant increase in colon tumor incidence relative to uninfected BALB-RagMin mice (23.5% versus 1.7%, respectively). The data suggest that H. hepaticus, which is present in many research colonies, promotes colon tumorigenesis in the BALB-RagMin mouse and that it has the potential to confound colon tumorigenesis studies.

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Figures

FIG. 1.

(A) Whole mount of gastrointestinal tract of an 11-month-old BALB-Min mouse. Asterisks identify dilatations in the small intestine. st, stomach; si, small intestine; ce, cecum; co, colon. (B) Mucosal surface of one of the dilatations in panel A, showing the presence of large, sessile adenomas (arrows). (C) Photomicrograph of BALB-Min small intestine adenoma showing IHC staining for β-catenin. Scale bar = 250 μm. (D) Photomicrograph of BALB-RagMin small intestine adenoma showing IHC staining for β-catenin. The IHC staining pattern is similar to that for BALB-Min (C). Scale bar = 250 μm. (E) Photomicrograph of liver of uninfected female, 7 months of age, BALB-RagMin. The liver disease index was 1.0/16.0. Scale bar = 100 μm. (F) Liver of female BALB-RagMin mouse at 24 wpi (7 months of age) with periportal hepatitis (arrow). The liver disease index was 10.5/16.0. Scale bar = 100 μm.

FIG. 2.

(A) Photomicrograph of a normal cecum from an uninfected BALB-RagMin mouse. Ki67-immunoreactive cells are localized to the lower third of the crypt. The cecal disease index was 0.5/8.0. (B) Photomicrograph of hyperplastic cecal tissue from an _H. hepaticus_-infected BALB-RagMin mouse at 24 wpi. Ki67-immunoreactive cells are present in the upper half of the crypt. The cecal disease index was 4.0/8.0. Scale bar = 100 μm.

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Helicobacter hepaticus infection promotes colon tumorigenesis in the BALB/c-Rag2(-/-) Apc(Min/+) mouse - PubMed (original) (raw)