Bacterial infection of smad3/rag2 double-null mice with transforming growth factor-β dysregulation as a model for studying inflammation-associated colon cancer

Maggio-Price, Lillian, Treuting, Piper, Bielefeldt-Ohmann. Helle, Seamons, Audrey, Drivdahl, Rolf, Zeng, Weiping, Lai, Lap Hin, Huycke, Mark, Phelps, Susan, Brabb, Thea and Iritani, Brain M. (2009) Bacterial infection of smad3/rag2 double-null mice with transforming growth factor-β dysregulation as a model for studying inflammation-associated colon cancer. American Journal of Pathology, 174 1: 317-329. doi:10.2353/ajpath.2009.080485


Author Maggio-Price, Lillian
Treuting, Piper
Bielefeldt-Ohmann. Helle
Seamons, Audrey
Drivdahl, Rolf
Zeng, Weiping
Lai, Lap Hin
Huycke, Mark
Phelps, Susan
Brabb, Thea
Iritani, Brain M.
Title Bacterial infection of smad3/rag2 double-null mice with transforming growth factor-β dysregulation as a model for studying inflammation-associated colon cancer
Journal name American Journal of Pathology   Check publisher's open access policy
ISSN 0002-9440
1525-2191
Publication date 2009-01-01
Year available 2009
Sub-type Article (original research)
DOI 10.2353/ajpath.2009.080485
Volume 174
Issue 1
Start page 317
End page 329
Total pages 13
Place of publication Seattle, U.S.
Publisher American Society for Investigative Pathology
Language eng
Subject 07 Agricultural and Veterinary Sciences
0707 Veterinary Sciences
C1
Abstract 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-{kappa}B activation, increased BclXL/Bcl-2 expression, increased c-Myc expression, accentuated epithelial cell proliferation, and up-regulated IFN-{gamma}, IL-1{alpha}, TNF-{alpha}, 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-{kappa}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.
Keyword Colon Cancer
Chronic inflammation
Smad3 - null mice
T lymphocytes
Helicobacter Infections
Immunohistochemistry
Macrophages uptake
Q-Index Code C1
Q-Index Status Provisional Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Veterinary Science Publications
 
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Created: Wed, 09 Dec 2009, 18:43:55 EST by Rosalind Blair on behalf of School of Veterinary Science