Gravaghi C, Bo J, Laperle K M D, Quimby F, Kucherlapati R, Edelmann W, Lamprecht S A
Division of Gastroenterology and Hepatology, Department of Medicine, Strang Cancer Research Laboratory, Weill Medical College of Cornell University, New York, NY, USA.
Int J Obes (Lond). 2008 Nov;32(11):1716-9. doi: 10.1038/ijo.2008.149. Epub 2008 Aug 26.
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-mLepr(db/db); Apc(1638N/+) 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 Apc(1638N/+) 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.
流行病学证据表明肥胖与人类结肠癌之间存在联系。通过给肥胖啮齿动物施用化学致癌物，对肥胖与结肠肿瘤发生之间的假定关联进行了实验探索。本研究的主要目的是培育出一种既表现出肥胖又表现出肠道肿瘤发生的新型小鼠品系。为此，我们培育出了同时携带db和Apc突变的C57BLKS-mLepr(db/db); Apc(1638N/+)小鼠。db突变导致肥胖和2型糖尿病，Apc突变是肠道肿瘤形成的关键起始事件。所有小鼠在6个月龄时实施安乐死，并对胃肠道的所有区域进行肿瘤检查。结果表明，Apc(1638N/+)和db突变的组合不仅增强了突变型Apc驱动的小肠肿瘤发生，还诱发了胃和结肠肿瘤。纯合db小鼠未发生胃肠道肿瘤。这些发现表明，与2型糖尿病相关的肥胖会促进Apc缺陷小鼠的胃肠道肿瘤发生，并为肥胖与结直肠癌之间的机制联系提供了证据。
