title: Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment.
abstract: Eicosanoids, including PGs, produced by cyclooxygenases (COX), and leukotrienes, produced by 5-lipoxygenase (5-LO) have been implicated in cancer progression. These molecules are produced by both cancer cells and the tumor microenvironment (TME). We previously reported that both COX and 5-LO metabolites increase during progression in an orthotopic immunocompetent model of lung cancer. Although PGs in the TME have been well studied, less is known regarding 5-LO products produced by the TME. We examined the role of 5-LO in the TME using a model in which Lewis lung carcinoma cells are directly implanted into the lungs of syngeneic WT mice or mice globally deficient in 5-LO (5-LO-KO). Unexpectedly, primary tumor volume and liver metastases were increased in 5-LO-KO mice. This was associated with an ablation of leukotriene (LT) production, consistent with production mainly mediated by the microenvironment. Increased tumor progression was partially reproduced in global LTC4 synthase KO or mice transplanted with LTA4 hydrolase-deficient bone marrow. Tumor-bearing lungs of 5-LO-KO had decreased numbers of CD4 and CD8 T cells compared with WT controls, as well as fewer dendritic cells. This was associated with lower levels of CCL20 and CXL9, which have been implicated in dendritic and T cell recruitment. Depletion of CD8 cells increased tumor growth and eliminated the differences between WT and 5-LO mice. These data reveal an antitumorigenic role for 5-LO products in the microenvironment during lung cancer progression through regulation of T cells and suggest that caution should be used in targeting this pathway in lung cancer.
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045;
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Poczobutt
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045;
authors.forename: Teresa T
authors.identifier: http://orcid.org/0000-0002-7211-4176
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045;
authors.forename: Dwight
authors.initials: D
authors.lastname: Hanson
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045; Veterans Affairs Medical Center, Denver, CO 80220; and.
authors.forename: Howard
authors.identifier: http://orcid.org/0000-0002-1230-2941
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045;
authors.forename: Trisha R
authors.initials: TR
authors.lastname: Sippel
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045; Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Mary C M
authors.initials: MC
authors.lastname: Weiser-Evans
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Miguel
authors.initials: M
authors.lastname: Gijon
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Robert C
authors.identifier: http://orcid.org/0000-0002-9430-6515
authors.initials: RC
authors.lastname: Murphy
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045; Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045 raphael.nemenoff@ucdenver.edu.
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Nemenoff
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency*; D018827:Carcinoma, Lewis Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000276:immunology / Q000473:pathology; D009368:Neoplasm Transplantation; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D001094:Arachidonate 5-Lipoxygenase