Abstract A104: IL6 signaling is required for pancreatitis-induced pancreatic intra-epithelial neoplasia progression and maintenance in mice.

Abstract

Background: Epidemiological and experimental data suggest a causal link between chronic pancreatitis and pancreatic cancer. The cytokine interleukin 6 (IL6) is upregulated during the course of pancreatitis; moreover, recent studies have shown that the cytokine interleukin 6 (IL6) plays a role in pancreatic cancer initiation and progression. Our goal was to investigate whether IL6 upregulation provides a causal link in pancreatitis-induced carcinogenesis in mice. Methods: We previously described the iKras* mouse as a new model of pancreatic tumorigenesis based on pancreas-specific expression of the oncogenic form of Kras, KrasG12D. By crossing iKras* mice with IL6-deficient mice we have generated iKras*; IL6-/-mice, as well as iKras*; IL6+/-. To induce pancreatitis, we injected the colecistokinin agonis Caerulein administered by intraperitoneal injection. The pancreatic tissue was collected at several time-points for histopathological analysis. In addition, the immune cells infiltrated were analyzed by flow cytometry. Results: 1] IL6 is required for pancreatitis induced PanIN maintenance. PanIN lesions arose from both iKras* and iKras*;IL6-/- mice 3 weeks post-pancreatitis. By 17 weeks after pancreatitis the iKras* pancreata were totally replaced by PanINs; however, iKras*; IL6-/- pancreata appeared atrophic, devoid of PanINs and largely populated by acini. Our data further suggest that, in absence of IL6, epithelial cell survival is affected in PanIN lesions. 2] IL6 is a key regulator of inflammation during carcinogenesis. Flow cytometry analysis revealed that fewer macrophage and myeloid-derived suppressor cells (MDSCs) were recruited to iKras*; IL6-/- pancreata 3 weeks post-pancreatitis. MDSCs have been involved in maintaining an immune-suppressive microenvironment in tumors. 3] Taking advantage of the reversible expression of KrasG12D in iKras* mice, we also show that deletion of IL6 signaling accelerates PanIN reprogramming (ductal to acinar redifferentiation) following Kras* inactivation. 4] Finally, in a set of in vitro 3-dimensional culture experiments, we show that IL6 promotes acinar-ductal metaplasia (ADM)/PanIN formation and progression in acinar clusters embedded in Matrigel. Conclusion: Previous studies had shown that IL6 signaling is required for the development of PanIN lesions in mice. Here, we show that IL6 is essential for PanIN maintenance following induction of acute pancreatitis. Thus, IL6 potentially represents a therapeutic target in pancreatic cancer. Citation Format: Yaqing Zhang, Filip Bednar, Wei Yan, Meredith Anne Collins, Sabita Rakshit, Marina Pasca Di Magliano. IL6 signaling is required for pancreatitis-induced pancreatic intra-epithelial neoplasia progression and maintenance in mice. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A104.