High-Fat, High-Calorie Diet Promotes Early Pancreatic Neoplasia in the Conditional KrasG12D Mouse Model

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. The goal of the present study was to develop a model of diet-induced obesity and pancreatic cancer development in a state-of-the-art mouse model, which resembles important clinical features of human obesity, e.g. weight gain and metabolic disturbances. Offspring of Pdx-1-Cre and LSL-KrasG12D mice were allocated to either a diet high in fats and calories (HFCD; ~4,535 kcal/kg; 40% of calories from fats) or control diet (CD; ~3,725 kcal/kg; 12% of calories from fats) for 3 months. Compared to control animals, mice fed the HFCD significantly gained more weight and developed hyperinsulinemia, hyperglycemia, hyperleptinemia, and elevated levels of IGF-1. The pancreas of HFCD-fed animals showed robust signs of inflammation with increased numbers of infiltrating inflammatory cells (macrophages and T-cells), elevated levels of several cytokines and chemokines, increased stromal fibrosis, and more advanced PanIN lesions. Our results demonstrate that a diet high in fats and calories leads to obesity and metabolic disturbances similar to humans and accelerates early pancreatic neoplasia in the conditional KrasG12D mouse model. This model and findings 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.

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

“…Encouragingly, however, recent attempts have been made to humanise the mouse immune system by ablating the endogenous immune system and engrafting human immune cells, or by transgenic expression of human immunoreceptor genes [49]. Notwithstanding the many limitations, the in vivo modelling of a tumour and its microenvironment in murine models has enabled important insights into the links between obesity and the hallmarks of cancer in myriad pathways, including the tumour stroma, [11,14,16], immune cell response [14,16,23,[31][32][33]39,46], and the local and systemic inflammatory response [16,24,39,41,42].…”

“…In oesophageal neoplasia, a Mendelian randomisation study demonstrated that humans with a genetic predisposition to obesity also had an increased risk of oesophageal neoplasia and dysplasia, suggesting a causal genetic link between the two [56]. Pdx-1-Cre and LSLKrasG12D mice HCFD Pancreas of HFCD " infiltrating inflammatory cells (macrophages and T cells), " levels of several cytokines and chemokines, " stromal fibrosis, and more advanced PanIN lesions [23] KrasG12D mice HCFD " Inflammation in visceral adipose tissue, particularly in peripancreatic fat [24] Other Breast Ovariectomized or shamoperated C3H/HeN HFD Energy excess in oestrogendeprived mice: " serum FFAs and insulin, tumour volume, InsR, mTOR, and pAKT/AKT ratios [10] …”

Robust Early Inflammation of the Peripancreatic Visceral Adipose Tissue During Diet-Induced Obesity in the KrasG12D Model of Pancreatic Cancer

“…In our previous studies we have demonstrated that a high fat, high calorie diet led to significant weight gain, metabolic disturbances, inflammation in the pancreas, and acceleration of pancreatic neoplasia in the conditional KrasG12D mouse model of pancreatic cancer 20 . In the current work, we provide evidence that in this mouse model obesity contributes to robust VAT inflammation, in particular in the peri-pancreatic fat, which may in turn be responsible for accelerating inflammation and neoplastic progression in the adjacent pancreas.…”

Mutant KRAS–Induced Expression of ICAM-1 in Pancreatic Acinar Cells Causes Attraction of Macrophages to Expedite the Formation of Precancerous Lesions

“…For example, it was demonstrated that caerulein-induced release of digestive enzymes and subsequent pancreatic inflammation in Kras G12D -expressing mice accelerates the development of PDA (4). Similarly, a high fat diet in Kras G12D -expressing mice dramatically accelerates PDA by causing pancreatic inflammation and macrophage infiltration (5). Consequently, in humans environmental risk factors for the development of pancreatic cancers are pancreatitis, and inducers of inflammatory responses such as obesity and smoking (6, 7).…”