Blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitis
Boryana K. Popivanova, … , Chifumi Fujii, Naofumi Mukaida
Boryana K. Popivanova, … , Chifumi Fujii, Naofumi Mukaida
Published January 24, 2008
Citation Information: J Clin Invest. 2008;118(2):560-570. https://doi.org/10.1172/JCI32453.
View: Text | PDF
Research Article

Blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitis

Abstract

The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To understand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-α expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced infiltration of macrophages and neutrophils, and attenuated subsequent tumor formation. WT mice transplanted with TNF-Rp55–deficient bone marrow also developed significantly fewer tumors after AOM and DSS treatment than either WT mice or TNF-Rp55–deficient mice transplanted with WT bone marrow. Furthermore, administration of etanercept, a specific antagonist of TNF-α, to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by neutrophils and macrophages. These observations identify TNF-α as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-α may be useful in treating colon cancer in individuals with UC.

Authors

Boryana K. Popivanova, Kazuya Kitamura, Yu Wu, Toshikazu Kondo, Takashi Kagaya, Shiuchi Kaneko, Masanobu Oshima, Chifumi Fujii, Naofumi Mukaida

×

Figure 5

COX-2 expression in the colons.

Options: View larger image (or click on image) Download as PowerPoint
COX-2 expression in the colons. (A) Quantitative RT-PCR was performed on...
(A) Quantitative RT-PCR was performed on total RNAs extracted from the colons at the indicated time intervals as described in Methods. The levels of COX-2 mRNA were normalized to the levels of GAPDH mRNA. **P < 0.01 versus untreated (control) mice. (B–D) Immunohistochemical and immunofluorescence detection of COX-2–expressing cells. Colons were obtained from WT mice at the indicated time intervals and processed for immunohistochemical analysis using anti–COX-2 antibodies, and representative results from 5 independent animals are shown in B. The numbers of COX-2–expressing cells were determined as described in Methods and are shown in C and expressed as mean ± SD. *P < 0.05, **P < 0.01 versus untreated. Double-color immunofluorescence analysis was performed with the combination of anti–COX-2 and anti–F4/80 (D, top row) or that of anti–COX-2 and anti-Ly6G antibodies (D, bottom row). Representative results from 5 independent experiments are shown here. Original magnification, ×400 (B); ×800 (D). Scale bars, 10 μm.