Rapid acceleration of pancreatic adenocarcinoma development by PPARδ hyperactivation
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a rising incidence in the United States and globally. Effective strategies to prevent and treat PDAC are urgently needed. The majority of PDACs arise from pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions.
Approximately 54–78% of adults older than 40 years are estimated to harbor low-grade PanINs; fortunately, the majority do not develop PDAC. Nonetheless, identification of key factors that promote progression of PanINs to PDAC is critical for the development of interventions that can effectively reduce the rising PDAC incidence.
High-fat diets (HFDs) have been associated with an increased risk of PDAC in humans. In studies of animal models, HFDs promote both chemically induced and mutant KrasG12D-initiated pancreatic carcinogenesis. HFDs are enriched with fatty acids that act as natural activating ligands of peroxisome proliferator-activated receptor-delta (PPARδ, encoded by PPARD). PPARδ is a transcriptional receptor that regulates the expression of a wide spectrum of key genes influencing important processes in cellular biology (e.g. lipid metabolism, carcinogenesis). PPARδ is upregulated in major human cancers, including pancreatic cancers. PPARδ upregulation in human pancreatic cancers correlates with higher pathological stages and a higher risk of metastasis. However, the effects of PPARδ on PanINs progression into PDAC, especially in relation to HFDs, remain poorly defined.
We became interested in studying the effects of PPARδ on pancreatic carcinogenesis following our prior observations that PPARδ strongly promoted other gastrointestinal cancers. There is currently very limited information regarding the role of PPARδ in PDAC development, and we felt that addressing this knowledge gap was very important. The excessive intake of HFDs can readily lead to PPARδ hyperactivation in PanINs. In addition, highly selective and potent synthetic PPARδ agonists (e.g. GW501516) have been pharmaceutically developed to treat non-cancerous conditions (e.g. obesity, hyperlipidemia). While large pharmaceutical companies have discontinued development of PPARδ agonists because of their potential pro-carcinogenic effects, PPARδ agonists are still being illicitly sold to athletes, for muscle endurance enhancement, via websites that fail to discuss their potential harmful effects.
Our findings in this article demonstrate that PanINs have higher PPARδ levels. Furthermore, activation of PPARδ by exposure to either natural (e.g., fatty acids in HFD) or synthetic (e.g., GW501516) ligands dramatically accelerate PanIN progression into PDAC in mice. Thus, PPARδ upregulation in PanINs can be a serious vulnerability that leads to PanIN progression to PDAC, when activated by either the natural or synthetic PPARδ ligands. This new information should alert individuals to a potentially serious health risk associated with the use of synthetic PPARδ agonists such as GW501516. Additionally, this finding could prompt individuals who might harbor PanINs to consider limiting their HFD intake. More importantly, development of effective agents to block PPARδ activation could be a new approach to prevent progression of PanINs to PDAC.