Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer
Author(s)
Mangerich, Aswin; Knutson, Charles G. F.; Parry, Nicola Maria Anne; Muthupalani, Sureshkumar; Ye, Wenjie; Prestwich, Erin; Cui, Liang; McFaline, Jose Luis; Mobley, Melissa W.; Ge, Zhongming; Taghizadeh, Koli; Wishnok, John S.; Wogan, Gerald N.; Fox, James G.; Tannenbaum, Steven Robert; Dedon, Peter C.; ... Show more Show less
DownloadWogan-2012-Infection-induced colitis in mice causes dynamic and.pdf (1.757Mb)
PUBLISHER_POLICY
Publisher Policy
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Terms of use
Metadata
Show full item recordAbstract
Helicobacter hepaticus-infected Rag2-/- mice emulate many aspects of human inflammatory bowel disease, including the development of colitis and colon cancer. To elucidate mechanisms of inflammation-induced carcinogenesis, we undertook a comprehensive analysis of histopathology, molecular damage, and gene expression changes during disease progression in these mice. Infected mice developed severe colitis and hepatitis by 10 wk post-infection, progressing into colon carcinoma by 20 wk post-infection, with pronounced pathology in the cecum and proximal colon marked by infiltration of neutrophils and macrophages. Transcriptional profiling revealed decreased expression of DNA repair and oxidative stress response genes in colon, but not in liver. Mass spectrometric analysis revealed higher levels of DNA and RNA damage products in liver compared to colon and infection-induced increases in 5-chlorocytosine in DNA and RNA and hypoxanthine in DNA. Paradoxically, infection was associated with decreased levels of DNA etheno adducts. Levels of nucleic acid damage from the same chemical class were strongly correlated in both liver and colon. The results support a model of inflammation-mediated carcinogenesis involving infiltration of phagocytes and generation of reactive species that cause local molecular damage leading to cell dysfunction, mutation, and cell death. There are strong correlations among histopathology, phagocyte infiltration, and damage chemistry that suggest a major role for neutrophils in inflammation-associated cancer progression. Further, paradoxical changes in nucleic acid damage were observed in tissue- and chemistry-specific patterns. The results also reveal features of cell stress response that point to microbial pathophysiology and mechanisms of cell senescence as important mechanistic links to cancer.
Description
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1207829109/-/DCSupplemental
Date issued
2012-06Department
Massachusetts Institute of Technology. Center for Environmental Health Sciences; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Chemistry; Massachusetts Institute of Technology. Division of Comparative Medicine; Singapore-MIT Alliance in Research and Technology (SMART)Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
National Academy of Sciences (U.S.)
Citation
Mangerich, A. et al. “PNAS Plus: Infection-induced Colitis in Mice Causes Dynamic and Tissue-specific Changes in Stress Response and DNA Damage Leading to Colon Cancer.” Proceedings of the National Academy of Sciences 109.27 (2012): E1820–E1829. Web.© 2013 National Academy of Sciences.
Version: Final published version
ISSN
0027-8424
1091-6490