Abstract 3095: Promotion of pancreatic cancer by perfluorooctanoic acid (PFOA)
Authors: Barbara A. Hocevar, Lisa M. Kamendulis
Journal: Cancer Research (2018)

Abstract Pancreatic cancer is the fourth leading cause of cancer deaths and one of the most lethal forms of cancer diagnosed in the United States. While the exact cause of pancreatic cancer is unknown, established risk factors for pancreatic cancer include smoking, alcohol consumption and pancreatitis; all of which share the ability to generate oxidative stress - a condition known to promote cancer progression. Perfluorooctanoic acid (PFOA), a chemical widely used in consumer and industrial applications, has been shown to induce pancreatic acinar cell tumors in rodents through a yet to be determined mechanism. In humans, epidemiologic studies have linked PFOA exposure to adverse chronic health effects including several types of cancer. PFOA has been detected in essentially all of the American population, with mean serum levels close to 4 ng/ml and a predicted half-life of ~ 4 yrs. We have previously shown that exposure of mice to PFOA for 7 days triggered oxidative stress in the pancreas, which was associated with focal ductal hyperplasia and inflammation. The purpose of this study was to determine if PFOA exposure promotes the progression of pancreatic cancer in a well-characterized mouse model of pancreatic cancer, the LSL-KRasG12D;Pdx-1 Cre model. For our studies, LSL-KRasG12D;Pdx-1Cre mice received either tap water or tap water supplemented with 5 ppm PFOA, starting at 2 months of age. Mice were sacrificed at 6 and 9 months of age, corresponding to 4 and 7 months of PFOA treatment, at which time serum and tissues were collected. Pancreata were processed for histologic examination (H&amp;E stain), immunohistochemistry for CK19, used as a marker to identify neoplastic lesion area, and RNA isolation for gene expression. Serum was utilized for quantitation of amylase, lipase, PFOA and inflammatory cytokine levels. Our preliminary results show that PFOA accumulates in the serum and pancreas of treated LSL-KRasG12D;Pdx-1 Cre mice. In addition, exposure to PFOA increased the CK19+ lesion area in LSL-KRasG12D;Pdx-1 Cre mice indicating an acceleration of pancreatic cancer progression. qPCR analysis of pancreata verified increased expression of both CK19 and the early lesion marker Sox9 in PFOA-treated mice. Analysis of mRNA expression in the pancreas revealed an increase in oxidative stress, evidenced by elevated Sod1 expression, and an increase in inflammatory markers (Tnfα and IL1α). Together, these results demonstrate that PFOA leads to expansion of the pancreatic lesion area in the LSL-KRasG12D;Pdx-1 Cre mouse model which is accompanied by oxidative stress and an inflammatory response. These results, coupled with the widespread human exposure to PFOA and its biological persistence, suggest that it could be a prominent agent promoting pancreatic cancer progession. Citation Format: Barbara A. Hocevar, Lisa M. Kamendulis. Promotion of pancreatic cancer by perfluorooctanoic acid (PFOA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3095.