title: Endotoxin induces proliferation of NSCLC in vitro and in vivo: role of COX-2 and EGFR activation.
abstract: Lung cancer is frequently complicated by pulmonary infections which may impair prognosis of this disease. Therefore, we investigated the effect of bacterial lipopolysaccharides (LPS) on tumor proliferation in vitro in the non-small cell lung cancer (NSCLC) cell line A549, ex vivo in a tissue culture model using human NSCLC specimens and in vivo in the A549 adenocarcinoma mouse model. LPS induced a time- and dose-dependent increase in proliferation of A549 cells as quantified by MTS activity and cell counting. In parallel, an increased expression of the proliferation marker Ki-67 and cyclooxygenase (COX)-2 was detected both in A549 cells and in ex vivo human NSCLC tissue. Large amounts of COX-2-derived prostaglandin (PG)E(2) were secreted from LPS-stimulated A549 cells. Pharmacological interventions revealed that the proliferative effect of LPS was dependent on CD14 and Toll-like receptor (TLR)4. Moreover, blocking of the epidermal growth factor receptor (EGFR) also decreased LPS-induced proliferation of A549 cells. Inhibition of COX-2 activity in A549 cells severely attenuated both PGE(2) release and proliferation in response to LPS. Synthesis of PGE(2) was also reduced by inhibiting CD14, TLR4 and EGFR in A549 cells. The proliferative effect of LPS on A549 cells could be reproduced in the A549 adenocarcinoma mouse model with enhancement of tumor growth and Ki-67 expression in implanted tumors. In summary, LPS induces proliferation of NSCLC cells in vitro, ex vivo in human NSCLC specimen and in vivo in a mouse model of NSCLC. Pulmonary infection may thus directly induce tumor progression 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: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.forename: Florentine S B
authors.initials: FS
authors.lastname: Subtil
authors.forename: Jochen
authors.initials: J
authors.lastname: Wilhelm
authors.forename: Anja
authors.initials: A
authors.lastname: Schmall
authors.forename: Dagmar S
authors.initials: DS
authors.lastname: Lang
authors.forename: Torsten
authors.initials: T
authors.lastname: Goldmann
authors.forename: Bastian
authors.initials: B
authors.lastname: Eul
authors.forename: Gabriele
authors.initials: G
authors.lastname: Dahlem
authors.forename: Ludger
authors.initials: L
authors.lastname: Fink
authors.forename: Ralph-Theo
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Gamal-Andre
authors.initials: GA
authors.lastname: Banat
authors.forename: Ulf
authors.initials: U
authors.lastname: Sibelius
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Vollmer
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grandel
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009578:Nitrobenzenes / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016861:Cyclooxygenase Inhibitors; D019394:Ki-67 Antigen; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C496512:Ptgs1 protein, mouse; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D015232:Dinoprostone; D007213:Indomethacin