Abstract
Epidemiological evidence indicates a link between obesity and human colon cancer. A putative association between obesity and colon tumorigenesis has been explored experimentally using chemical carcinogens administered to obese rodents. The main objective of this study was to generate a new mouse line that displays both obesity and intestinal tumorigenesis. To this end, we have generated C57BLKS-mLeprdb/db; Apc1638N/+ mice combining both db and Apc mutations. The db mutation results in obesity and type 2 diabetes, the Apc mutation is a key initiating event of intestinal neoplasia. All mice were euthanized at 6 months of age and all regions of the gastrointestinal tract examined for tumors. The results show that the combination of Apc1638N/+ and db mutations not only enhanced mutant Apc-driven small intestinal tumorigenesis but also induced gastric and colonic tumors. Homozygous db mice did not develop gastrointestinal neoplasia. These findings indicate that obesity associated with type 2 diabetes promotes gastrointestinal tumorigenesis in Apc-deficient mice and provides evidence of a mechanistic link between obesity and colorectal neoplasia.
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Acknowledgements
This study was supported by grants from National Institutes of Health, (Postdoctoral Fellowship R25 to C Gravaghi, #CA-84301 to R Kucherlapati); National Cancer Institute (#RO1 CA76329 and #U54 CA100926 to W Edelmann) and a grant from The Irving Weinstein Foundation, Inc. USA (SA Lamprecht). We thank Dr K Zhou (Division of Biostatistics and Epidemiology, Department of Public Health, Weill Medical College of Cornell University, NY, USA) for statistical advice, M Peppas (Strang Cancer Research Laboratory, NY) for assistance in animal care and maintenance and Dr G Benigno (LSE, London School of Economics, London, UK) for revising the figures. We have no competing financial interest.
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Gravaghi, C., Bo, J., LaPerle, K. et al. Obesity enhances gastrointestinal tumorigenesis in Apc-mutant mice. Int J Obes 32, 1716–1719 (2008). https://doi.org/10.1038/ijo.2008.149
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DOI: https://doi.org/10.1038/ijo.2008.149
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