How Does a High-Fat Diet Contribute to Pancreatic Cancer?

A high-fat diet can promote development of pancreatic cancer, but cyclooxygenase-2 (COX2) inhibitors prevent this process, according to a mouse study published in the December issue of Gastroenterology. The mechanisms appear to involve activation of oncogenic KRAS and upregulation of COX2, which promotes pancreatic inflammation.

Increased body mass index and excessive body weight are risk factors for pancreatic ductal adenocarcinoma (PDAC). This is a concern, because the number of obese individuals in the United States has doubled to 59 million during the past 2 decades. Increasing consumption of high-fat diets is contributing to the prevalence of obesity. Bincy Philip et al. investigated whether high-fat diets promote development of PDAC in mice.

Mice that express oncogenic Kras (which contains the activating G12D mutation) specifically in acinar cells (LSL-Kras/Ela-CreERT mice) develop pancreatic intraepithelial neoplasia (PanINs)—the initial step in the progression of PDAC, although at a very low rate.

The G12D mutation in KRAS is believed to be involved in the earliest stages of transformation of normal pancreatic acinar cells into PanINs. However, the mutation has been detected in a large number of healthy people who never develop PDAC, so other factors must be involved. Oncogenic KRAS is believed to require further stimuli to transform cells.

Philip et al. investigated whether the high-fat diet might be the stimulus that oncogenic KRAS needs to promote development of pancreatic cancer.

They placed LSL-Kras/Ela-CreERT mice on either control diets, in which 10% of energy comes from fat, or high-fat diets, in which 60% of energy is derived from fat.

The mice fed control diets formed a few spontaneous PanIN at young ages. However, mice fed the high-fat diets developed pancreatic inflammation and fibrosis and higher numbers of PanINs and PDACs than the mice fed control diets. The high-fat diet mice all died by 250 days, while about 70% of the mice on control diets were still alive. Pancreata of mice that did not express oncogenic Kras but were also fed high-fat diets had minor pathologic alterations.

Pancreatic tissues from LSL-Kras/Ela-CreERT mice on high-fat diets had increased levels of Kras activity than mice on control diets. The authors state that these findings support the concept that oncogenic Kras is largely inactive until stimulated, and that a high-fat diet provides the signal for full Kras activation.

High activity of Kras can promote inflammation via several mechanisms, including COX2. Philip et al. tested whether COX2 was required for high-fat diet-induced changes in pancreatic tissues.

They found that mice that expressed oncogenic Kras but had targeted deletion of COX2 in pancreatic acinar cells had no evidence of increased numbers of PanIN lesions, inflammation, or fibrosis after 30 days on high-fat diets.

Mice expressing oncogenic Kras were then placed on high-fat diets but also given celecoxib, a selective COX2 inhibitor, for 38 days. These mice had significantly lower levels of inflammation, fibrosis, and PanIN development than mice on high-fat diets given saline instead of celecoxib.

The authors conclude that a high-fat diet provides the stimulus needed to fully activate oncogenic Kras, which along with COX2 expression contributes to PDAC initiation (see below figure).

Activation of oncogenic Kras leads to activation of COX2, phosphorylation of ERK, infiltration of macrophages (blue) into the stroma, and activation of quiescent stellate cells (pink), which produce α-SMA and collagen I to promote fibrosis. COX2 is part a feedback loop that maintains Kras activity and promotes further inflammation.

Activation of oncogenic Kras leads to activation of COX2, phosphorylation of ERK, infiltration of macrophages (blue) into the stroma, and activation of quiescent stellate cells (pink), which produce α-SMA and collagen I to promote fibrosis. COX2 is part a feedback loop that maintains Kras activity and promotes further inflammation.

Philip et al. propose that COX2 is part a feedback loop that maintains Kras activity and promotes further fibrosis and inflammation in the pancreas. The findings provide insight into the connection between obesity and PDAC development, as well as interesting strategies to prevent PDAC.

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