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.
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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

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Figure 1

Tumor formation in WT and TNF-Rp55–/– (TNF-Rp55KO) mice after AOM and DSS treatment.

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Tumor formation in WT and TNF-Rp55–/– (TNF-Rp55KO) mice after AOM and DS...
(A) Schematic overview of this colon carcinogenesis model. (B) Macroscopical changes in colon. Colons were removed at day 56 from treated WT and TNF-Rp55–/– mice, and representative results from 10 independent animals are shown here. (C) The numbers of tumors. Colons were removed at day 56 to determine the numbers of macroscopic tumors. Each value represents the mean ± SD (n = 10 animals). **P < 0.01 versus WT. (D). TNF-α gene expression in the colons of WT mice. The levels of TNF-α mRNA were quantified by quantitative RT-PCR as described in Methods, and normalized to the level of GAPDH mRNA. *P < 0.05, **P < 0.01 versus untreated (control) mice. (E and F) Immunohistochemical detection of TNF-α and TNF-Rp55 in colons. Colons were obtained from WT mice at the indicated time intervals; insets are higher magnification of the positively stained cells as indicated by arrows. Representative results from 6 independent experiments are shown here (original magnification, ×400; ×1,000 [insets]).