Abstract 4847: Alcoholic chronic pancreatitis increases tissue transformed macrophages (M2) which promote pancreatic cancer lesions in a Kras mouse model

Abstract

Abstract Background: Alcoholic chronic pancreatitis (ACP) is a major risk factor for pancreatic cancer; however, the mechanism through which it promotes cancer is not known. In this study we developed a mouse model of pancreatic cancer induced by ACP and analyzed the effect of the interaction between macrophages and pancreatic cancer cells on progression of the disease. Methods: Pdx1-Cre;LSL-Kras transgenic and wild-type (WT) mice were fed Lieber DeCarli control or alcohol diet for 6 weeks. Mice were subjected to 7-hourly cerulein injections (50µg/kg) twice a week for the last 3 weeks of the diet to induce chronic pancreatitis. Pancreatic intraepithelial neoplastic (PanIN) lesions, proliferation, fibrosis, inflammation, EMT and stem cell markers were analyzed by immunohistochemistry and Western. Monocytes/ macrophages from mice and their conditioned medium were applied to the pancreatic cancer cell line MIA PaCa-2. Cell survival and apoptosis were measured by MTT and ELISA. Expression of cytokines/ chemokines and growth factors by cancer cells and macrophages was measured by multiplex assay analysis. Results: ACP increased fibrosis, stellate cell activation and inflammation in both WT and transgenic mouse pancreata. The increases were significantly greater in the transgenic mice. Further, ACP increased the number and stage of PanIN lesions in the pancreata of transgenic mice. EMT markers were stimulated by ACP in both WT and transgenic mice. Markers of type 2 macrophages (M2) were greater in ACP model compared to control mice. M2 macrophages conditioned media stimulated proliferation, EMT and cancer stemness in cancer cells. Cancer cells or PanIN cells conditioned media stimulated transformation of macrophages to the type 2 phenotype. Conclusion: The results indicate that ACP promotes pancreatic cancer progression in transgenic mice. Our data suggest ACP as well as PanIN and cancer cells stimulate the phenotype change of macrophages toward type 2, which then stimulates cancer cell proliferation, EMT and cancer stemness. These results suggest that tissue macrophages play a key role in the increased risk for pancreatic cancer in patients with alcoholic pancreatitis. Citation Format: Mouad Edderkaoui, Paul Grippo, Hajar Benhaddou, Yassine Ouhaddi, Hidekazu Tsukamoto, Steven Swartwood, Beatrice Knudsen, Helen S. Goodridge, Aida Habtezion, Vay-Liang Go, Stephen J. Pandol. Alcoholic chronic pancreatitis increases tissue transformed macrophages (M2) which promote pancreatic cancer lesions in a Kras mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4847. doi:10.1158/1538-7445.AM2014-4847