Lawrence M Knab1, Michelle Schultz2, Daniel R Principe3, Windel E Mascarinas2, Elias Gounaris3, Hidayatullah G Munshi4, Paul J Grippo2, David J Bentrem5. 1. Division of Surgical Oncology, Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address: l-knab@northwestern.edu. 2. Department of Medicine, University of Illinois-Chicago, Chicago, Illinois. 3. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. 4. Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois; Department of Surgery, Jesse Brown VA Medical Center, Chicago, Illinois. 5. Division of Surgical Oncology, Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois; Department of Surgery, Jesse Brown VA Medical Center, Chicago, Illinois.
Abstract
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), which continues to have a dismal prognosis, is associated with a pronounced fibroinflammatory response. Inflammation in vivo can be mediated by 5-lipoxygenase (5LO), an enzyme that converts omega-6 fatty acids (FA) to eicosanoids, including leukotriene B4 (LTB4). We have previously shown that diets rich in omega-6 FA increase pancreatic lesions and mast cell infiltration in EL-Kras mice. In this study, we evaluated the role of 5LO in generating higher levels of LTB4 from human cells and in mediating lesion development and mast cell infiltration in EL-Kras mice. MATERIALS AND METHODS: Human pancreatic ductal epithelial and cancer cells were treated with omega-6 FA in vitro. EL-Kras mice lacking 5LO (EL-Kras/5LO(-/-)) mice were generated and fed standard chow or omega-6 FA diets. Pancreatic lesion frequency and mast cell infiltration were compared with EL-Kras/5LO(+/+) mice. Human PDAC tumors were evaluated for 5LO expression and mast cells. RESULTS: Human pancreatic ductal epithelial and pancreatic cancer cells treated with omega-6 FA generated increased LTB4 levels in vitro. EL-Kras/5LO(-/-) mice developed fewer pancreatic lesions and had decreased mast cell infiltration when compared with EL-Kras/5LO(+/+) mice. Human PDAC tumors with increased 5LO expression demonstrate increased mast cell infiltration. Additionally, diets rich in omega-6 FA failed to increase pancreatic lesion development and mast cell infiltration in EL-Kras/5LO(-/-) mice. CONCLUSIONS: The expansion of mutant Kras-induced lesions via omega-6 FA is dependent on 5LO, and 5LO functions downstream of mutant Kras to mediate inflammation, suggesting that 5LO may be a potential chemopreventive and therapeutic target in pancreatic cancer.
BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC), which continues to have a dismal prognosis, is associated with a pronounced fibroinflammatory response. Inflammation in vivo can be mediated by 5-lipoxygenase (5LO), an enzyme that converts omega-6 fatty acids (FA) to eicosanoids, including leukotriene B4 (LTB4). We have previously shown that diets rich in omega-6 FA increase pancreatic lesions and mast cell infiltration in EL-Krasmice. In this study, we evaluated the role of 5LO in generating higher levels of LTB4 from human cells and in mediating lesion development and mast cell infiltration in EL-Krasmice. MATERIALS AND METHODS:Humanpancreatic ductal epithelial and cancer cells were treated with omega-6 FA in vitro. EL-Krasmice lacking 5LO (EL-Kras/5LO(-/-)) mice were generated and fed standard chow or omega-6 FA diets. Pancreatic lesion frequency and mast cell infiltration were compared with EL-Kras/5LO(+/+) mice. HumanPDACtumors were evaluated for 5LO expression and mast cells. RESULTS:Humanpancreatic ductal epithelial and pancreatic cancer cells treated with omega-6 FA generated increased LTB4 levels in vitro. EL-Kras/5LO(-/-) mice developed fewer pancreatic lesions and had decreased mast cell infiltration when compared with EL-Kras/5LO(+/+) mice. HumanPDACtumors with increased 5LO expression demonstrate increased mast cell infiltration. Additionally, diets rich in omega-6 FA failed to increase pancreatic lesion development and mast cell infiltration in EL-Kras/5LO(-/-) mice. CONCLUSIONS: The expansion of mutant Kras-induced lesions via omega-6 FA is dependent on 5LO, and 5LO functions downstream of mutant Kras to mediate inflammation, suggesting that 5LO may be a potential chemopreventive and therapeutic target in pancreatic cancer.
Authors: Mingfeng Zhang; Soren Lykke-Andersen; Bin Zhu; Wenming Xiao; Jason W Hoskins; Xijun Zhang; Lauren M Rost; Irene Collins; Martijn van de Bunt; Jinping Jia; Hemang Parikh; Tongwu Zhang; Lei Song; Ashley Jermusyk; Charles C Chung; Bin Zhu; Weiyin Zhou; Gail L Matters; Robert C Kurtz; Meredith Yeager; Torben Heick Jensen; Kevin M Brown; Halit Ongen; William R Bamlet; Bradley A Murray; Mark I McCarthy; Stephen J Chanock; Nilanjan Chatterjee; Brian M Wolpin; Jill P Smith; Sara H Olson; Gloria M Petersen; Jianxin Shi; Laufey Amundadottir Journal: Gut Date: 2017-06-20 Impact factor: 23.059
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