High-Fat Diet Drives an Aggressive Pancreatic Cancer Phenotype

Abstract

Emerging evidence indicates associations between high-fat diet (HFD), metabolic syndrome (MetS), and increased risk of pancreatic cancer. However, individual components of an HFD that increase cancer risk have not been isolated. In addition, a specific pattern of cytokine elevation by which MetS drives pancreatic tumor progression is not well described. We hypothesized that oleic acid (OA), a major component of HFD, would augment pancreatic neoplastic processes. An orthotopic pancreatic cancer model with Panc02cells was used to compare the effect of low-fat diet to OA-based HFD on cancer progression. Tumors were quantitated, analyzed by immunohistochemistry. In addition, serum cytokine levels were quantitated. Proliferation, migration assays, and expression of epithelial-to-mesenchymal transition factors were evaluated on Panc02 and MiaPaCa-2 pancreatic cancer cells cultured in high concentrations of OA. HFD tumor-bearing mice (n=8) had an 18% weight increase (P<0.001) and increased tumor burden (P<0.05) compared with the low-fat diet tumor-bearing group (n=6). HFD tumors had significantly increased angiogenesis (P<0.001) and decreased apoptosis (P<0.05). Serum of HFD mice demonstrated increased levels of glucagon and glucagon-like peptide-1. Two pancreatic cancer cell lines cultured in OA demonstrated significant increases in proliferation (P<0.001) and a >2.5-fold increase in cell migration (P<0.001) when treated with OA. Panc02 treated with OA had increased expression of epithelial-to-mesenchymal transition factors SNAI-1 (Snail) and Zeb-1(P<0.01). High-fat conditions invitro and invivo resulted in an aggressive pancreatic cancer phenotype. Our data support further investigations elucidating molecular pathways augmented by MetS conditions to identify novel therapeutic strategies for pancreatic cancer.