Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer
The retinoblastoma gene (Rb) is mutated at significant frequency in various human epithelial tumors, including colorectal cancer, and is strongly associated with metastatic disease. However, sole inactivation of Rb in the mouse has so far failed to yield epithelial cancers. Here, we specifically ina...
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2016
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| Online Access: | http://hdl.handle.net/1721.1/105724 https://orcid.org/0000-0001-9451-2194 |
| _version_ | 1826217684798275584 |
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| author | Bronson, R T Parisi, Tiziana Lees, Jacqueline |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Bronson, R T Parisi, Tiziana Lees, Jacqueline |
| author_sort | Bronson, R T |
| collection | MIT |
| description | The retinoblastoma gene (Rb) is mutated at significant frequency in various human epithelial tumors, including colorectal cancer, and is strongly associated with metastatic disease. However, sole inactivation of Rb in the mouse has so far failed to yield epithelial cancers. Here, we specifically inactivate Rb and/or p53 in the urogenital epithelium and the intestine. We find that loss of both tumor suppressors is unable to yield tumors in the transitional epithelium lining the bladder, kidneys and ureters. Instead, these mice develop highly metastatic tumors of neuroendocrine, not epithelial, origin within the urogenital tract to give prostate cancer in the males and vaginal tumors in the females. Additionally, we discovered that the sole inactivation of Rb in the intestine was sufficient to induce formation of metastatic colorectal adenocarcinomas. These tumors closely mirror the human disease in regard to age of onset, histological appearance,
invasiveness and metastatic potential. Like most human colorectal carcinomas, our murine Rbdeficient tumors demonstrate genomic instability and they show activation of β-catenin. Deregulation of the Wnt/β-catenin pathway is specific to the intestinal tumors, as genomic instability but not activation of β-catenin was observed in the neuroendocrine tumors. To date,
attempts to generate genetically engineered mouse models of colorectal cancer tumors have yielded mostly cancer of the small intestine, which rarely occurs in humans. Our system provides the opportunity to accurately model and study colorectal cancer in the mouse via a single gene mutation. |
| first_indexed | 2024-09-23T17:07:31Z |
| format | Article |
| id | mit-1721.1/105724 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:07:31Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
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| spelling | mit-1721.1/1057242022-10-03T10:35:56Z Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer Bronson, R T Parisi, Tiziana Lees, Jacqueline Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Parisi, Tiziana Lees, Jacqueline The retinoblastoma gene (Rb) is mutated at significant frequency in various human epithelial tumors, including colorectal cancer, and is strongly associated with metastatic disease. However, sole inactivation of Rb in the mouse has so far failed to yield epithelial cancers. Here, we specifically inactivate Rb and/or p53 in the urogenital epithelium and the intestine. We find that loss of both tumor suppressors is unable to yield tumors in the transitional epithelium lining the bladder, kidneys and ureters. Instead, these mice develop highly metastatic tumors of neuroendocrine, not epithelial, origin within the urogenital tract to give prostate cancer in the males and vaginal tumors in the females. Additionally, we discovered that the sole inactivation of Rb in the intestine was sufficient to induce formation of metastatic colorectal adenocarcinomas. These tumors closely mirror the human disease in regard to age of onset, histological appearance, invasiveness and metastatic potential. Like most human colorectal carcinomas, our murine Rbdeficient tumors demonstrate genomic instability and they show activation of β-catenin. Deregulation of the Wnt/β-catenin pathway is specific to the intestinal tumors, as genomic instability but not activation of β-catenin was observed in the neuroendocrine tumors. To date, attempts to generate genetically engineered mouse models of colorectal cancer tumors have yielded mostly cancer of the small intestine, which rarely occurs in humans. Our system provides the opportunity to accurately model and study colorectal cancer in the mouse via a single gene mutation. National Cancer Institute (U.S.) (Grants P30-CA14051, P01-CA42063 and RO1-CA121921) 2016-12-05T21:07:23Z 2016-12-05T21:07:23Z 2015-03 2014-11 Article http://purl.org/eprint/type/JournalArticle 0950-9232 1476-5594 http://hdl.handle.net/1721.1/105724 Parisi, T, R T Bronson, and J A Lees. “Inactivation of the Retinoblastoma Gene Yields a Mouse Model of Malignant Colorectal Cancer.” Oncogene 34.48 (2015): 5890–5899. https://orcid.org/0000-0001-9451-2194 en_US http://dx.doi.org/10.1038/onc.2015.30 Oncogene Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Nature Publishing Group PMC |
| spellingShingle | Bronson, R T Parisi, Tiziana Lees, Jacqueline Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer |
| title | Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer |
| title_full | Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer |
| title_fullStr | Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer |
| title_full_unstemmed | Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer |
| title_short | Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer |
| title_sort | inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer |
| url | http://hdl.handle.net/1721.1/105724 https://orcid.org/0000-0001-9451-2194 |
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