title: Ablation of 5-lipoxygenase mitigates pancreatic lesion development.
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.
  
  
  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.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address: l-knab@northwestern.edu.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Knab
authors.affiliation: Department of Medicine, University of Illinois-Chicago, Chicago, Illinois.
authors.forename: Michelle
authors.initials: M
authors.lastname: Schultz
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Principe
authors.affiliation: Department of Medicine, University of Illinois-Chicago, Chicago, Illinois.
authors.forename: Windel E
authors.initials: WE
authors.lastname: Mascarinas
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
authors.forename: Elias
authors.initials: E
authors.lastname: Gounaris
authors.affiliation: 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.
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
authors.affiliation: Department of Medicine, University of Illinois-Chicago, Chicago, Illinois.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Grippo
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000209:etiology*; D045744:Cell Line, Tumor; D043371:Fatty Acids, Omega-6 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism*; D008407:Mast Cells / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000209:etiology*; D059016:Tumor Microenvironment
chemical_list: D043371:Fatty Acids, Omega-6; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase
keywords: 5-Lipoxygenase; Inflammation; Omega-6 fatty acids; Pancreatic cancer