Obesity enhances gastrointestinal tumorigenesis in Apc-mutant mice.
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.
Gravaghi
C
C
Division of Gastroenterology and Hepatology, Department of Medicine, Strang Cancer Research Laboratory, Weill Medical College of Cornell University, New York, NY, USA.
Bo
J
J
Laperle
K M D
KM
Quimby
F
F
Kucherlapati
R
R
Edelmann
W
W
Lamprecht
S A
SA
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology*; D041981:Gastrointestinal Tract / Q000473:pathology; D017491:Genes, APC; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000473:pathology*