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 6

The effects of a TNF antagonist, etanercept, on colon carcinogenesis.

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The effects of a TNF antagonist, etanercept, on colon carcinogenesis. (A...
(A) Schematic overview of etanercept administration. Colons were removed at day 67 after the mice were administered etanercept (Et) or a vehicle control between days 56 and 60. (B) The tumor sizes and numbers were determined macroscopically. The bars represent the median of each group. Each symbol represents the tumor numbers of each animal or the average size of the tumors of each animal. (C) Macroscopic evaluation of the tumors. Colons were removed on day 67 from WT mice, treated with etanercept or with vehicle. Representative results from 10 independent animals are shown here. Original magnification, ×6. (D) Colons were processed for hematoxylin and eosin staining and representative results from 5 independent animals are shown here. Original magnification, ×40. (E and F) Myeloperoxidase- (E) and F4/80-positive cells (F) were enumerated as described in Methods. All values represent the mean ± SD (n = 10 animals). *P < 0.05, **P < 0.01 versus etanercept-untreated WT mice. (G and H) Quantitative RT-PCR analysis for KC/CXCL1 (G) and MCP-1/CCL2 (H) was performed on total RNAs extracted from the colons at the indicated time intervals as described in Methods. KC/CXCL1 and MCP-1/CCL2 mRNA levels were normalized to the levels of GAPDH mRNA. *P < 0.05, **P < 0.01 versus etanercept untreated WT mice.