As the fourth leading cause of cancer deaths in the United States, pancreatic cancer is one of the most lethal forms of cancer diagnosed. While the exact cause of pancreatic cancer is unknown, several risk factors have been identified as potential contributors to pancreatic cancer, including environmental factors such as smoking, drinking, diet, and exposure to environmental chemicals. Chronic exposure to perfluorooctanoic acid (PFOA) results in the induction of pancreatic cancer in rodents through an undefined mechanism. Due to the widespread human exposure to PFOA and its biological persistence, it is critical to understand how PFOA promotes pancreatic cancer in rodents. The objective in this application is to determine the biological mechanism through which PFOA promotes pancreatic cancer. The central hypothesis, based on strong preliminary data, is that PFOA exposure leads to ER and oxidative stress, which leads to acinar cell damage and inflammation, resulting in acinar to ductal metaplasia (ADM) and the promotion of pancreatic cancer.
Three specific aims have been developed to test this hypothesis.
Aim 1 will determine the time- and dose- dependent effects of PFOA on the promotion of pancreatic cancer using the well-established LSL-KRasG12D; Pdx-1 Cre mouse model. At two months of age, mice will be untreated or treated with PFOA followed by histological assessment of tumor progression at selected time-points, which will be correlated with PFOA levels and measures of oxidative stress.
Aim 2 will determine whether PFOA exposure results in the generation of ER stress, leading to oxidative stress and inflammation. PFOA-mediated ER stress will be assessed using a combination of cell culture-based treatments, short term PFOA treatment in C57Bl/6 mice and PFOA treatment of KRasG12D mice which will be correlated with oxidative stress measurements. It will also be determined whether prevention of ER stress mitigates PFOA-stimulated oxidative stress.
Aim 3 will determine whether PFOA exposure accelerates the process of ADM and/or increases the occurrence of ADM events. ADM, an early precursor lesion observed in pancreatic cancer progression will be evaluated in wild-type acinar cells and acinar cells which express KRasG12D in 2D and 3D cell cultures to assess whether PFOA treatment accelerates ADM and/or increases ADM events. The proposed research is innovative, as it will be the first to mechanistically identify the biological pathways and the doses at which PFOA exposure elicits ER and oxidative stress in the pancreas, and the first to evaluate the ability of an environmental chemical to promote pancreatic cancer progression in the KRasG12D genetic model. This contribution is significant, because identifying the mechanism for the induction of oxidative stress by PFOA will enable the development of strategies to prevent adverse health outcomes related to oxidative stress elicited by chemicals such as PFOA. Furthermore, these studies will enhance the research environment at the applicant?s institution and provide opportunities for engagement of undergraduate and graduate students in pancreatic cancer research.
- PUBLIC HEALTH While the exact causes of pancreatic cancer are unknown, chemical exposures have been identified as risk factors in epidemiological studies. Perfluorooctanoic acid (PFOA), a persistent environmental chemical that causes pancreatic cancer in rodents, has been identified in serum all residents of the US; thus, this project is relevant to public health because identification of the mechanism of PFOA-mediated promotion of pancreatic cancer is needed to adequately evaluate the risk of exposure to this chemical in humans. The proposed research is relevant to the mission of the NCI to conduct and support research and training with respect to the cause, prevention and treatment of cancer.
