Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1207829109/-/DCSupplemental
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2013
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| Online Access: | http://hdl.handle.net/1721.1/76720 https://orcid.org/0000-0002-5811-6853 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0003-0771-9889 https://orcid.org/0000-0001-9307-6116 https://orcid.org/0000-0002-2325-552X https://orcid.org/0000-0002-4607-5337 |
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| author | 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. |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences 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. |
| author_sort | Mangerich, Aswin |
| collection | MIT |
| description | This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1207829109/-/DCSupplemental |
| first_indexed | 2024-09-23T12:44:34Z |
| format | Article |
| id | mit-1721.1/76720 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:44:34Z |
| publishDate | 2013 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/767202022-09-28T09:46:32Z Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer 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. 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) 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. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1207829109/-/DCSupplemental 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. Cancer Research Institute (CA026731) National Institute of Environmental Health Sciences (5T32-ES007020-34, Training Grant in Toxicology) National Institute of Environmental Health Sciences (ES002109) Massachusetts Institute of Technology (Merck-MIT Fellowship) German Academic Exchange Service 2013-02-04T20:16:34Z 2013-02-04T20:16:34Z 2012-06 2012-03 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/76720 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. https://orcid.org/0000-0002-5811-6853 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0003-0771-9889 https://orcid.org/0000-0001-9307-6116 https://orcid.org/0000-0002-2325-552X https://orcid.org/0000-0002-4607-5337 en_US http://dx.doi.org/10.1073/pnas.1207829109 Proceedings of the National Academy of Sciences of the United States of America 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. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | 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. Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer |
| title | Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer |
| title_full | Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer |
| title_fullStr | Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer |
| title_full_unstemmed | Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer |
| title_short | Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer |
| title_sort | infection induced colitis in mice causes dynamic and tissue specific changes in stress response and dna damage leading to colon cancer |
| url | http://hdl.handle.net/1721.1/76720 https://orcid.org/0000-0002-5811-6853 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0003-0771-9889 https://orcid.org/0000-0001-9307-6116 https://orcid.org/0000-0002-2325-552X https://orcid.org/0000-0002-4607-5337 |
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