Background: Obesity is postulated to be a major risk factor for pancreatic ductal carcinoma (PDAC), which is the fourth deadliest cancer in the US. Although the association between obesity and pancreatic cancer has been reported, the molecular mechanisms are not yet known. Since K-Ras mutations are almost universal in PDAC, and we have recently shown that endogenous levels of oncogenic K-Ras make cells susceptible to otherwise benign levels of inflammation, we hypothesize that high fat intake can act as a persistent low level inflammatory mechanism capable of inducing PDAC in cells expressing a single copy of oncogenic K-Ras. In the current study, we examined the effects of high dietary fat on the development of precancerous lesions and fibrosis, as well as the activation of K-Ras signaling pathways in mice expressing mutant K-Ras in pancreatic acinar cells.
Methods: Transgenic mice LSL-K-Ras were cross with Ela-CreER (Pancreatic-Ras) and treated with tamoxifen to “knock-in” oncogenic K-Ras in adult pancreatic acinar cells. Pancreatic-Ras and littermate control mice were administered a low fat diet with 10.2% kcal fat or a high fat diet with 61.6% kcal fat for 30 days starting at 50 days of age. Mice were then sacrificed and analyzed histologically for fibrosis development, presence of precancerous lesions, and activation of K-Ras signaling pathways.
Results: Mice expressing endogenous levels of oncogenic K-Ras and fed a high fat diet developed abundant fibrosis, low grade precancerous lesions throughout the pancreas and had higher levels of phospho-ERK when compared to littermate controls and mice fed a low fat diet.
Conclusions: These findings suggest that consumption of high dietary fat acts as an inflammatory stimulus that enhances the activation of oncogenic K-Ras downstream signaling pathways, leading to the early development of precancerous lesions and fibrosis in the pancreas. Therefore, efforts aimed at inhibiting inflammation and K-Ras activation would be expected to prevent cancer development.
Citation Format: Zobeida Cruz-Monserrate, Bincy Philips, Baoan Ji, Jaroslaw Daniluk, Craig D. Logsdon. High-fat diet accelerates development of precancerous lesions and fibrosis in mice expressing mutant K-Ras in pancreatic acinar cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B113.