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Infection and Immunity, June 2008, p. 2758-2766, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01604-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Helicobacter hepaticus Infection Promotes Colon Tumorigenesis in the BALB/c-Rag2^–/– Apc^Min/+ Mouse

Claude M. Nagamine,^1, Jane J. Sohn,^2, Barry H. Rickman,^1, Arlin B. Rogers,¹ James G. Fox,^1,2 and David B. Schauer^1,2*

Division of Comparative Medicine,¹ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts²

Received 5 December 2007/ Returned for modification 23 January 2008/ Accepted 1 April 2008

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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* Corresponding author. Mailing address: Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Bldg. 56-787, Cambridge, MA 02139. Phone: (617) 253-8113. Fax: (617) 258-0225. E-mail: schauer{at}mit.edu

Published ahead of print on 14 April 2008.

Editor: B. A. McCormick

Present address: Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA 94305-5410.

Present address: Molecular Genetics and Carcinogenesis Section, National Cancer Institute, Bethesda, MD 20892.

Present address: San Diego County Animal Disease Diagnostic Laboratory, Department of Agriculture, Weights and Measures, San Diego, CA 92123.

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Infection and Immunity, June 2008, p. 2758-2766, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01604-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.