|
Back to 2016 Annual Meeting
Visceral Pre-Adipocytes From Obese Krasg12d Mice Stimulate Proliferation of Pancreatic Intraepithelial Neoplasms
Mu Xu*1, Xiaoman Jung1, Hui-Hua Chang1, Aune Moro1, Alexander Stark1, Andrea I. Schmidt1,2, Guido Eibl1, Oscar J. Hines1
1Surgery, UCLA, Los Angeles, CA; 2General and Visceral Surgery,, University Hospital Freiburg, Freiburg, Germany
Background: Obesity has been associated with multiple types of cancer. Our previous work has shown that a HFCD leads to obesity in mice with inflammation of the visceral adipose tissue and pancreas. In the transgenic KrasG12D (KC) mouse model, HFCD also accelerates the development of pancreatic neoplasia, suggesting that visceral obesity may play an active, rather than a permissive role in pancreatic cancer development. In this study we aimed to investigate the effects of visceral adipose tissue on the proliferation of pancreatic intraepithelial neoplasm (PanIN) cells in vitro.
Methods: Primary pre-adipocytes were isolated from visceral adipose tissue depots of wildtype (WT) and KC mice fed either the control diet (CD) or HFCD and cultured ex vivo. PanIN cells isolated from KC mice were incubated with the supernatant of pre-adipocyte cultures for 24 hours. DNA synthesis was evaluated by the thymidine incorporation assay as a measure of cell proliferation. We further stained these supernatant-exposed PanIN cells with anti-Ki-67 and anti-7-AAD antibodies and used fluorescence-activated cell sorting (FACS) to analyze cell cycle distribution.
Results: Supernatant from pre-adipocytes isolated from WT and KC mice on CD had a similar effect in stimulating PanIN proliferation. The thymidine incorporation of PanIN cells from the KC-CD group was 1.3-fold (range 1.0-1.4, p>0.05), compared to the WT-CD group. However, pre-adipocyte supernatant from KC mice on HFCD significantly increased PanIN proliferation (2.0 fold, range 1.7-2.4 fold, p<0.05; Figure 1). This increase in DNA synthesis was associated with a nearly 2-fold higher percentage of PanIN cells entering the S-phase in the HFCD group than the CD group (6.2% vs. 3.7%; Figure 2).
Conclusions: Our results demonstrate that visceral pre-adipocytes from KC mice fed a HFCD have a more robust effect on PanIN proliferation than pre-adipocytes from WT mice and KC mice on a CD. This suggests that cytokine(s) secreted by the pre-adipocytes from obese KC mice stimulate PanIN cell growth by accelerating G1/S transition. Our results indicate a potentially important promoting effect of visceral adipose tissue on PanIN cell growth in the KC mouse model, and could constitute an important mechanism, by which diet-induced obesity can accelerate pancreatic cancer development.
 
Back to 2016 Annual Meeting
|
