Bacterial infection of Smad3/Rag2 double-null mice with transforming growth factor-beta dysregulation as a model for studying inflammation-associated colon cancer.
Alterations in genes encoding transforming growth factor-beta-signaling components contribute to colon cancer in humans. Similarly, mice deficient in the transforming growth factor-beta 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-kappaB activation, increased Bcl(XL)/Bcl-2 expression, increased c-Myc expression, accentuated epithelial cell proliferation, and up-regulated IFN-gamma, IL-1alpha, TNF-alpha, IL-1beta, 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-kappaB 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.
Maggio-Price
Lillian
L
Department of Comparative Medicine, University of Washington, School of Medicine, Seattle, Washington 98195, USA. lmprice@u.washington.edu
Treuting
Piper
P
Bielefeldt-Ohmann
Helle
H
Seamons
Audrey
A
Drivdahl
Rolf
R
Zeng
Weiping
W
Lai
LapHin
L
Huycke
Mark
M
Phelps
Susan
S
Brabb
Thea
T
Iritani
Brian M
BM
D000230:Adenocarcinoma / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D000818:Animals; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016481:Helicobacter Infections / Q000150:complications* / Q000276:immunology; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000172:deficiency* / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta