Diet-Induced Obesity Is Associated With Increased Levels Of Il-4 And Il-13, Macrophage Infiltration, Fibrosis, And Pancreatic Neoplasia In The Conditional Krasg12d Mouse Model

Background: Obesity is a well known risk factor for the development of several cancers including pancreatic cancer (PaCa). The formation of an inflammatory microenvironment with a complex communication between (pre)-neoplastic cells and stromal cells, including fibroblasts and inflammatory cells, is thought to promote tumor development during obesity. However, the exact molecular signals that are critical in this process are unknown. Recently, there has been interest in understanding the role of interleukins (IL)-4 and -13 in mediating the crosstalk between several cell types in cancer. E.g. they have been shown to promote the conversion of anti-tumorigenic M1 macrophages to pro-tumorigenic M2 macrophages. Aim: In this study we sought to investigate whether diet-induced obesity in the conditional KrasG12D mouse model of PaCa is associated with enhanced fibrosis and inflammation in the pancreas and to determine a possible role of IL-4 and -13. Methods and Results: Conditional KrasG12D mice and wildtype controls were fed a high fat, high calorie diet (HFCD) or control diet (CD) for 3 months. Mice fed the HFCD gained significantly more weight with a substantial enlargement of the visceral adipose tissue. Mutant mice fed the HFCD had more advanced pancreatic intraepithelial neoplasia lesions (PanINs). Compared to CD, mice fed the HFCD had a significant increase in pancreatic fibrosis (3.0±0.7 fold) and enhanced activation of pancreatic stellate cells (1.9±0.2) as assessed by immunohistochemical staining for fibronectin and α-smooth muscle actin, respectively. Flow cytometry demonstrated increased infiltration of Gr-CD11b+ macrophages (2.0±0.4 fold) into the pancreas in mice fed the HFCD. In addition, compared to the CD the HFCD was associated with increased tissue levels of IL-4 (43±5%) and IL-13 (65±20%) in the pancreas. Conclusion: Our results demonstrate that diet-induced obesity was associated with enhanced pancreatic neoplasia, inflammation, and fibrosis in the conditional KrasG12D mouse model. Our data further show that IL-4 and IL-13 are elevated in the pancreas of obese mice suggesting that these cytokines play a role, possibly in conversion of macrophages to the pro-tumorigenic M2 phenotype thereby promoting inflammation and tumor development. Citation Format: Chiara Birtolo, Guido Eibl, Aune Moro, Xiaoman Jung, Susan Morvaridi, Richard Waldron, Aurelia Lugea, Vay LW Go, Stephen J. Pandol. Diet-induced obesity is associated with increased levels of IL-4 and IL-13, macrophage infiltration, fibrosis, and pancreatic neoplasia in the conditional KrasG12D mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3163. doi:10.1158/1538-7445.AM2015-3163