title: Role of Cyclooxygenase-2 on Intermittent Hypoxia-Induced Lung Tumor Malignancy in a Mouse Model of Sleep Apnea.
abstract: An adverse role for obstructive sleep apnea (OSA) in cancer epidemiology and outcomes has recently emerged from clinical and animal studies. In animals, intermittent hypoxia (IH) mimicking OSA promotes tumor malignancy both directly and via host immune alterations. We hypothesized that IH could potentiate cancer aggressiveness through activation of the cyclooxygenase-2 (COX-2) pathway and the concomitant increases in prostaglandin E2 (PGE2). The contribution of the COX-2 in IH-induced enhanced tumor malignancy was assessed using celecoxib as a COX-2 specific inhibitor in a murine model of OSA bearing Lewis lung carcinoma (LLC1) tumors. Exposures to IH accelerated tumor progression with a tumor associated macrophages (TAMs) shift towards a pro-tumoral M2 phenotype. Treatment with celecoxib prevented IH-induced adverse tumor outcomes by inhibiting IH-induced M2 polarization of TAMs. Furthermore, TAMs isolated from IH-exposed mice treated with celecoxib reduced the proliferation of LLC1 naïve cells, while the opposite occurred with placebo-treated IH-exposed mice. Finally, in vitro IH exposures of murine macrophages and LLC1 cells showed that both cell types increased PGE2release in response to IH. These results suggest a crucial role for the COX-2 signaling pathway in the IH-exacerbated malignant processes, and designate macrophages and lung adenocarcinoma cells, as potential sources of PGE2.
authors.affiliation: Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, 08036-Barcelona, Spain.|Institute for Bioengineering of Catalonia, 08028-Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, 28029-Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Campillo
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, 28029-Madrid, Spain.|Laboratori del Son. Servei de Pneumologia, Hospital Clinic, Universitat de Barcelona 08036-Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Torres
authors.affiliation: Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, 08036-Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Vilaseca
authors.affiliation: Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, 08036-Barcelona, Spain.
authors.forename: Paula Naomi
authors.initials: PN
authors.lastname: Nonaka
authors.affiliation: Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gozal
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, 28029-Madrid, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036-Barcelona, Spain.|Department of Pneumology and Respiratory Allergy, Hospital Clinic, 08036-Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Roca-Ferrer
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, 28029-Madrid, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036-Barcelona, Spain.|Department of Pneumology and Respiratory Allergy, Hospital Clinic, 08036-Barcelona, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Picado
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, 28029-Madrid, Spain.|Laboratori del Son. Servei de Pneumologia, Hospital Clinic, Universitat de Barcelona 08036-Barcelona, Spain.
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Montserrat
authors.affiliation: Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, 08036-Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, 28029-Madrid, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036-Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Farré
authors.affiliation: Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, 08036-Barcelona, Spain.|Institute for Bioengineering of Catalonia, 08028-Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, 28029-Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Navajas
authors.affiliation: Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, 08036-Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, 28029-Madrid, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036-Barcelona, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Almendros
mesh_terms: D000818:Animals; D000068579:Celecoxib / Q000494:pharmacology; D016764:Cell Polarity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D000860:Hypoxia / Q000150:complications*; D007109:Immunity / Q000187:drug effects; D008175:Lung Neoplasms / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects / Q000378:metabolism; D009361:Neoplasm Invasiveness; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D012891:Sleep Apnea Syndromes / Q000150:complications* / Q000201:enzymology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism
chemical_list: D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone