M. Xu1, X. Jung1, A. Moro1, C. Chou1, H. Chang1, A. P. Stark1, A. Schmidt1, Y. Chen1, J. King1, O. J. Hines1, G. Eibl1 1University Of California – Los Angeles,Surgery,Los Angeles, CA, USA
Introduction: Obesity has been associated with multiple types of cancer. Our previous work has shown that a high-fat, high-calorie diet (HFCD) leads to obesity in conditional KrasG12D (KC) mice with inflammation of the visceral adipose tissue (VAT) and acceleration of pancreatic intraepithelial neoplasia (PanIN) development. In this study, we investigated whether diet-independent inflammation in the visceral adipose tissue is sufficient to accelerate pancreatic cancer (PDAC) development using hormone-sensitive lipase (hsl) deficient mice. Hsl is one of the enzymes involved in the hydrolysis of stored triglycerides. Non-obese hsl deficient mice are characterized by a significant inflammation in visceral adipose tissue.
Methods: KC mice were crossed into an hsl deficient background to generate KC;hsl+/+ and KC;hsl-/- mice. Mice were fed regular chow for six months and body weight recorded weekly. At sacrifice tissues were harvested for histological and immunohistochemical analysis.
Results: Over the study period of six months KC;hsl+/+ and KC;hsl-/- mice displayed similar weight gain. KC;hsl-/- males had an average weight of 29.5±4.5g at sacrifice, whereas KC;hsl+/+ males weighed 29.7±3.2g. KC;hsl-/- and KC;hsl+/+ females had an average weight of 25.2±1.8g and 24.3±1.8g, respectively. Twenty percent of the KC;hsl-/- mice developed invasive PDAC (n=20), whereas none of the KC;hsl+/+ mice developed PDAC (n=23; p<0.05). Interestingly, all KC;hsl-/- mice with PDAC were male. Histological and immune-histochemical analyses revealed that compared to KC;hsl+/+ mice KC;hsl-/- mice had significantly increased VAT inflammation as measured by the number of crown-like structures per high power field (hpf) (4.6±3.0 in KC;hsl-/- vs. 0.2±0.6 in KC;hsl+/+; p<0.01), enhanced activation of pancreatic stellate cells assessed by counting the cells per hpf positive for alpha-smooth muscle actin (44.5±9.0 in KC;hsl-/- vs. 15.8±5.2 in KC;hsl+/+; p<0.01) and more F4/80 positive macrophages per hpf in the pancreas (18.8±9.1 in KC;hsl-/- vs. 11.5±6.7 in KC;hsl+/+; p<0.01). PanIN lesions in KC;hsl-/- mice showed a higher rate of proliferation (per hpf) as measured by Ki67 staining (14.9±6.4 in KC;hsl-/- vs. 5.5±3.6 in KC;hsl+/+; p<0.01).
Conclusions: KC;hsl-/- mice had a significantly more robust VAT and pancreatic inflammation and accelerated PDAC development compared to KC;hsl+/+ mice. Our results suggest that VAT inflammation plays an important role in PDAC development.