Models and Mechanisms of High-Fat Diet (HFD) Promotion of Pancreatic Cancer

Abstract

There is epidemiologic evidence that obesity increases the risk of cancers. Several underlying mechanisms, including inflammation and insulin resistance, are proposed. However, the driving mechanisms in pancreatic cancer are poorly understood. In this chapter, we discuss models and mechanisms of diet-induced obesity and pancreatic cancer development. The focus is on a state-of-the-art mouse model, the conditional KrasG12D mouse model. High-fat, high-calorie diet-fed animals showed early pancreatic neoplasia and important clinical features of human obesity, including weight gain and metabolic disturbances such as hyperinsulinemia, hyperglycemia, hyperleptinemia, and elevated levels of insulin-like growth factor (IGF1). Consequently, the signal transduction pathways initiated by insulin/IGF-induced in pancreatic cancer cells, including the PI3K/Akt/mTORC1, are discussed. The high-fat, high-calorie diet-fed conditional KrasG12D mouse model will provide the basis for more robust studies attempting to unravel the mechanisms underlying the cancer-promoting properties of obesity, as well as to evaluate dietary- and chemo-preventive strategies targeting obesity-associated pancreatic cancer development.