title: Interactions between neutrophils and non-small cell lung cancer cells: enhancement of tumor proliferation and inflammatory mediator synthesis.
abstract: The inflammatory tumor microenvironment plays a crucial role in tumor progression. In lung cancer, both bacterial infections and neutrophilia are associated with a poor prognosis. In this study, we characterized the effect of isolated human neutrophils on proliferation of the non-small cell lung cancer (NSCLC) cell line A549 and analyzed the impact of A549-neutrophil interactions on inflammatory mediator generation in naive and lipopolysaccharide (LPS)-exposed cell cultures. Co-incubation of A549 cells with neutrophils induced proliferation of resting and LPS-exposed A549 cells in a dose-dependent manner. In transwell-experiments, this effect was demonstrated to depend on direct cell-to-cell contact. This pro-proliferative effect of neutrophils on A549 cells could be attenuated by inhibition of neutrophil elastase activity, but not by oxygen radical neutralization. Correspondingly, neutrophil elastase secretion, but not respiratory burst, was specifically enhanced in co-cultures of A549 cells and neutrophils. Moreover, interference with COX-2 activity by indomethacin or the specific COX-2 inhibitor NS-398 also blunted the increased A549 proliferation in the presence of neutrophils. In parallel, a massive amplification of COX-2-dependent prostaglandin E2 synthesis was detected in A549-neutrophil co-cultures. These findings suggest that direct cell-cell interactions between neutrophils and tumor cells cause release of inflammatory mediators which, in turn, may enhance tumor growth in NSCLC.
authors.affiliation: Department of Internal Medicine IV/V, University of Giessen and Marburg Lung Center (UGMLC), Klinikstrasse 33, Giessen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Hattar
authors.forename: Katharina
authors.initials: K
authors.lastname: Franz
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.forename: Ulf
authors.initials: U
authors.lastname: Sibelius
authors.forename: Jochen
authors.initials: J
authors.lastname: Wilhelm
authors.forename: Jürgen
authors.initials: J
authors.lastname: Lohmeyer
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.forename: Florentine S B
authors.initials: FS
authors.lastname: Subtil
authors.forename: Gabriele
authors.initials: G
authors.lastname: Dahlem
authors.forename: Bastian
authors.initials: B
authors.lastname: Eul
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grandel
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology*; D048708:Cell Growth Processes / Q000276:immunology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008175:Lung Neoplasms / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology*; D009578:Nitrobenzenes / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019272:Leukocyte Elastase; D015232:Dinoprostone