| Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment. | |
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MedLine Citation:
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PMID: 20080688 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Most genetically engineered mouse (GEM) models for colon cancer are based on tissuewide or germline gene modification, resulting in tumors predominantly of the small intestine. Several of these models involve modification of the adenomatous polyposis coli (Apc) gene and are excellent models for familial cancer predisposition syndromes. We have developed a stochastic somatic mutation model for sporadic colon cancer that presents with isolated primary tumors in the distal colon and recapitulates the entire adenoma-carcinoma-metastasis axis seen in human colon cancer. Using this model, we have analyzed tumors that are either solely mutant in the Apc gene or in combination with another colon cancer-associated mutant gene, the Kras G12D allele. Because of the restricted location in the distal colon, the natural history of the tumors can be analyzed by serial colonoscopy. As the mammalian target of rapamycin (mTOR) pathway is a critical component of the complex signaling network in colon cancer, we used this model to assess the efficacy of mTOR blockade through rapamycin treatment of mice with established tumors. After treatment, Apc mutant tumors were more than 80% smaller than control tumors. However, tumors that possessed both Apc and Kras mutations did not respond to rapamycin treatment. These studies suggest that mTOR inhibitors should be further explored as potential colorectal cancer therapies in patients whose tumors do not have activating mutations in KRAS. |
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Authors:
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Kenneth E Hung; Marco A Maricevich; Larissa Georgeon Richard; Wei Y Chen; Michael P Richardson; Alexandra Kunin; Roderick T Bronson; Umar Mahmood; Raju Kucherlapati |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-01-04 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 107 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2010-02-05 Completed Date: 2010-03-12 Revised Date: 2010-09-28 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 1565-70 Citation Subset: IM |
Affiliation:
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Division of Gastroenterology, Tufts Medical Center, Boston, MA 02111, USA. khung@tuftsmedicalcenter.org |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibiotics, Antineoplastic / therapeutic use* Colonic Neoplasms / drug therapy*, genetics, metabolism, pathology* Disease Models, Animal* Disease Progression Genes, APC Intracellular Signaling Peptides and Proteins / antagonists & inhibitors, metabolism Mice Mice, Knockout Mutation Neoplasm Metastasis Protein-Serine-Threonine Kinases / antagonists & inhibitors, metabolism Proto-Oncogene Proteins p21(ras) / genetics, metabolism Signal Transduction Sirolimus / therapeutic use* |
| Grant Support | |
ID/Acronym/Agency:
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5K08DK078033/DK/NIDDK NIH HHS; 5P50CA127003/CA/NCI NIH HHS; 5R01EB001872/EB/NIBIB NIH HHS; 5U01CA084301/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Intracellular Signaling Peptides and Proteins; 53123-88-9/Sirolimus; EC 2.7.1.-/mTOR protein; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 3.6.5.2/Kras2 protein, mouse; EC 3.6.5.2/Proto-Oncogene Proteins p21(ras) |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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