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(American Journal of Pathology. 2009;174:317-329.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080485

Bacterial Infection of Smad3/Rag2 Double-Null Mice with Transforming Growth Factor-β Dysregulation as a Model for Studying Inflammation-Associated Colon Cancer

Lillian Maggio-Price^*, Piper Treuting^*, Helle Bielefeldt-Ohmann, Audrey Seamons^*, Rolf Drivdahl^*, Weiping Zeng, LapHin Lai, Mark Huycke^¶, Susan Phelps^*, Thea Brabb^* and Brian M. Iritani^*

From the Department of Comparative Medicine,^* University of Washington, Seattle, Washington; the Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado; Seattle Genetics, Incorporated, Bothell, Washington; the Fred Hutchinson Cancer Research Center, Seattle, Washington; and the Medical Service,^¶ Departments of Veterans Medical Center and Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Alterations in genes encoding transforming growth factor-β-signaling components contribute to colon cancer in humans. Similarly, mice deficient in the transforming growth factor-β signaling molecule, Smad3, develop colon cancer, but only after a bacterial trigger occurs, resulting in chronic inflammation. To determine whether Smad3-null lymphocytes contribute to increased cancer susceptibility, we crossed Smad3-null mice with mice deficient in both B and T lymphocytes (Rag2^–/– mice). Helicobacter-infected Smad3/Rag2-double knockout (DKO) mice had more diffuse inflammation and increased incidence of adenocarcinoma compared with Helicobacter-infected Smad3^–/– or Rag2^–/– mice alone. Adoptive transfer of WT CD4⁺CD25⁺ T-regulatory cells provided significant protection of Smad3/Rag2-DKO from bacterial-induced typhlocolitis, dysplasia, and tumor development, whereas Smad3^–/– T-regulatory cells provided no protection. Immunohistochemistry, real-time reverse transcriptase-polymerase chain reaction, and Western blot analyses of colonic tissues from Smad3/Rag2-DKO mice 1 week after Helicobacter infection revealed an influx of macrophages, enhanced nuclear factor-B activation, increased Bcl_XL/Bcl-2 expression, increased c-Myc expression, accentuated epithelial cell proliferation, and up-regulated IFN-, IL-1, TNF-, IL-1β, and IL-6 transcription levels. These results suggest that the loss of Smad3 increases susceptibility to colon cancer by at least two mechanisms: deficient T-regulatory cell function, which leads to excessive inflammation after a bacterial trigger; and increased expression of proinflammatory cytokines, enhanced nuclear factor-B activation, and increased expression of both pro-oncogenic and anti-apoptotic proteins that result in increased cell proliferation/survival of epithelial cells in colonic tissues.