NDLI: Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment.

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Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Sippel, Trisha R. Gijon, Miguel Poczobutt, Joanna M. Nemenoff, Raphael A. Nguyen, Teresa T. Hanson, Dwight Weiser-Evans, Mary C. M. Murphy, Robert C. Li, Howard
Description	Author Affiliation: Poczobutt JM ( Department of Medicine, University of Colorado Denver, Aurora, CO 80045); Nguyen TT ( Department of Medicine, University of Colorado Denver, Aurora, CO 80045); Hanson D ( Department of Medicine, University of Colorado Denver, Aurora, CO 80045); Li H ( Department of Medicine, University of Colorado Denver, Aurora, CO 80045); Sippel TR ( Department of Medicine, University of Colorado Denver, Aurora, CO 80045); Weiser-Evans MC ( Department of Medicine, University of Colorado Denver, Aurora, CO 80045); Gijon M ( Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045.); Murphy RC ( Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045.); Nemenoff RA ( Department of Medicine, University of Colorado Denver, Aurora, CO 80045)
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.
ISSN	00221767
e-ISSN	15506606
DOI	10.4049/jimmunol.1501648
Journal	The Journal of Immunology
Issue Number	2
Volume Number	196
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2016-01-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Arachidonate 5-lipoxygenase Deficiency Carcinoma, Lewis Lung Pathology Lung Neoplasms Immunology T-lymphocytes Tumor Microenvironment Animals Enzymology Disease Models, Animal Disease Progression Flow Cytometry Immunohistochemistry Mice Mice, Inbred C57bl Mice, Knockout Neoplasm Invasiveness Neoplasm Transplantation Real-time Polymerase Chain Reaction Research Support, N.i.h., Extramural Research Support, U.s. Gov't, Non-p.h.s. Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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