title: Gram-positive pneumonia augments non-small cell lung cancer metastasis via host toll-like receptor 2 activation.
abstract: Surgical resection of early stage nonsmall cell lung cancer (NSCLC) is necessary for cure. However, rates of postoperative bacterial pneumonias remain high and may confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory cascade by recognizing microbial products at the surface of numerous cell types in the lung; however, little is known about how host TLRs influence NSCLC metastasis. TLR2 recognizes gram-positive bacterial cell wall components activating innate immunity. We demonstrate that lower respiratory tract infection with Streptococcus pneumonia augments the formation of murine H59 NSCLC liver metastases in C57BL/6 mice through host TLR2 activation. Infected mice demonstrate increased H59 and human A549 NSCLC adhesion to hepatic sinusoids in vivo compared with noninfected controls, a response that is significantly diminished in TLR2 knock-out mice. Intra-tracheal injection of purified TLR2 ligand lipoteichoic acid into mice similarly augments in vivo adhesion of H59 cells to hepatic sinusoids. Additionally, H59 and A549 NSCLC cells incubated with bronchoepithelial conditioned media show increased cell adhesion to extracellular matrix components in vitro and hepatic sinusoids in vivo in a manner that is dependent on bronchoepithelial TLR2 activation and interleukin-6 secretion. TLR2 is therefore a potential therapeutic target for gram-positive pneumonia-driven NSCLC metastasis.
authors.affiliation: Deparment of Surgery, L.D. MacLean Surgical Research Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Stephen D
authors.identifier: 0000-0003-0875-9540
authors.initials: SD
authors.lastname: Gowing
authors.affiliation: Deparment of Surgery, L.D. MacLean Surgical Research Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Chow
authors.affiliation: Deparment of Surgery, L.D. MacLean Surgical Research Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Cools-Lartigue
authors.affiliation: Deparment of Surgery, L.D. MacLean Surgical Research Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Crystal B
authors.initials: CB
authors.lastname: Chen
authors.affiliation: Deparment of Surgery, L.D. MacLean Surgical Research Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Najmeh
authors.affiliation: Deparment of Surgery, L.D. MacLean Surgical Research Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Henry Y
authors.initials: HY
authors.lastname: Jiang
authors.affiliation: Deparment of Surgery, L.D. MacLean Surgical Research Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: France
authors.initials: F
authors.lastname: Bourdeau
authors.affiliation: Department of Critical Care and Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Beauchamp
authors.affiliation: Deparment of Surgery, L.D. MacLean Surgical Research Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Ugo
authors.initials: U
authors.lastname: Mancini
authors.affiliation: Department of Critical Care and Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Angers
authors.affiliation: Deparment of Surgery, L.D. MacLean Surgical Research Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Betty
authors.initials: B
authors.lastname: Giannias
authors.affiliation: Deparment of Surgery, L.D. MacLean Surgical Research Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Spicer
authors.affiliation: Department of Medicine, Meakins-Christie Laboratories, McGill University Health Center, McGill University, Montreal, QC, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Rousseau
authors.affiliation: Department of Critical Care and Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Salman T
authors.initials: ST
authors.lastname: Qureshi
authors.affiliation: Deparment of Surgery, L.D. MacLean Surgical Research Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Lorenzo E
authors.initials: LE
authors.lastname: Ferri
mesh_terms: D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology / Q000473:pathology*; D002448:Cell Adhesion; D049109:Cell Proliferation; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008113:Liver Neoplasms / Q000209:etiology / Q000556:secondary*; D008175:Lung Neoplasms / Q000209:etiology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000150:complications* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000472:pathogenicity*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D008070:Lipopolysaccharides; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
keywords: gram-positive bacteria; lung cancer; metastasis; pneumonia; toll-like receptors