Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. Export

@article{citeulike:3824568, 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-alpha 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-alpha, 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-alpha as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-alpha may be useful in treating colon cancer in individuals with UC.}, author = {Popivanova, B. K. and Kitamura, K. and Wu, Y. and Kondo, T. and Kagaya, T. and Kaneko, S. and Oshima, M. and Fujii, C. and Mukaida, N.}, citeulike-article-id = {3824568}, citeulike-linkout-0 = {http://dx.doi.org/10.1172/JCI32453}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18219394}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18219394}, doi = {10.1172/JCI32453}, issn = {0021-9738}, journal = {The Journal of clinical investigation}, keywords = {cancer, colitis}, month = {February}, number = {2}, pages = {560--570}, posted-at = {2008-12-26 16:51:07}, priority = {2}, title = {Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis.}, url = {http://dx.doi.org/10.1172/JCI32453}, volume = {118}, year = {2008} }

TY - JOUR ID - citeulike:3824568 L3 - citeulike-article-id:3824568 N2 - 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-alpha 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-alpha, 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-alpha as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-alpha may be useful in treating colon cancer in individuals with UC. IS - 2 JF - The Journal of clinical investigation SN - 0021-9738 EP - 570 TI - Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. VL - 118 SP - 560 KW - cancer KW - colitis AU - Popivanova, BK AU - Kitamura, K AU - Wu, Y AU - Kondo, T AU - Kagaya, T AU - Kaneko, S AU - Oshima, M AU - Fujii, C AU - Mukaida, N PY - 2008/02// UR - http://dx.doi.org/10.1172/JCI32453 ER -