3rd Annual BMRP Investigator Meeting - Abstract

Helicobacter Infection Synergizes with Impaired TGFβ Signaling  to Induce Colon Cancer in Mice Deficient in SMAD3

Lillian Maggio-Price^1,a, Piper Treuting¹, Weiping Zeng¹, Mark Tsang¹, Helle Bielefeldt-Ohmann² and Brian Iritani<sup>1

1</sup>Department of Comparative Medicine and ²Washington National Primate Research Center, University of Washington (Seattle, Washington, U.S.A.)

Patients with Crohn’s disease (CD) and ulcerative colitis (UC) are at increased risk for developing colorectal cancer.  Transforming growth factor-beta (TGF-b) regulates intestinal epithelial cell proliferation and differentiation, and dysregulation of TGF-b signaling has been associated with CD, UC and colon cancer.  Because luminal microflora can affect the development of UC and CD, we wished to test the hypothesis that certain bacteria play a critical role in the development of colon cancer by interacting with commonly mutated pathways in human colon cancer.  In this study, we examined the role of intestinal helicobacter infections in the development of colon cancer in SMAD3 knockout mice (smad3 ^exo2/exo2), which exhibit abnormal TGF-b signaling and have previously been reported to manifest metastatic colonic carcinoma (Zhu et al. Cell, 1998.  We found that smad3^exo2/exo2 mice, when housed in a Helicobacter-free environment for up to nine months, do not manifest the previously-reported colon cancer phenotype.  However, infection of these smad^3exo2/exo2 mice with H. bilis and H. hepaticus triggers colon cancer in about 60% of the animals.  Interestingly, the highest concentration (as determined by real-time PCR) of Helicobacter organisms was found in the ceco-colic junction, which is the precise location of the mucinous adenocarcinomas.  Tumors developed at 10-32 weeks post-infection and were preceded by an early inflammatory phase with animals developing typhlocolitis which later resolved.  Immunohistochemical characterization of tumors showed increased numbers of Cox-2⁺ and CD4⁺ cells and of F4/80+ macrophages while no changes in beta-catenin expression were apparent.  These experiments suggest that infection with a particular bacterial organism like Helicobacter spp. can synergize with a disrupted TGF-b signaling pathway to induce colon cancer.  These results corroborate the notion that bacterial triggers may be important in human colorectal cancer, notably in the context of gene mutations in the TGF-b signaling pathway, one of the most common mutations found in colorectal cancer in humans.

^aPrincipal Investigator