title: Silica-induced chronic inflammation promotes lung carcinogenesis in the context of an immunosuppressive microenvironment.
abstract: The association between inflammation and lung tumor development has been clearly demonstrated. However, little is known concerning the molecular events preceding the development of lung cancer. In this study, we characterize a chemically induced lung cancer mouse model in which lung cancer developed in the presence of silicotic chronic inflammation. Silica-induced lung inflammation increased the incidence and multiplicity of lung cancer in mice treated with N-nitrosodimethylamine, a carcinogen found in tobacco smoke. Histologic and molecular analysis revealed that concomitant chronic inflammation contributed to lung tumorigenesis through induction of preneoplastic changes in lung epithelial cells. In addition, silica-mediated inflammation generated an immunosuppressive microenvironment in which we observed increased expression of programmed cell death protein 1 (PD-1), transforming growth factor-β1, monocyte chemotactic protein 1 (MCP-1), lymphocyte-activation gene 3 (LAG3), and forkhead box P3 (FOXP3), as well as the presence of regulatory T cells. Finally, the K-RAS mutational profile of the tumors changed from Q61R to G12D mutations in the inflammatory milieu. In summary, we describe some of the early molecular changes associated to lung carcinogenesis in a chronic inflammatory microenvironment and provide novel information concerning the mechanisms underlying the formation and the fate of preneoplastic lesions in the silicotic lung.
authors.affiliation: Center for Applied Medical Research (CIMA), Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Freire
authors.forename: Daniel
authors.initials: D
authors.lastname: Ajona
authors.forename: Gabriel
authors.initials: G
authors.lastname: de Biurrun
authors.forename: Jackeline
authors.initials: J
authors.lastname: Agorreta
authors.forename: Victor
authors.initials: V
authors.lastname: Segura
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Guruceaga
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Bleau
authors.forename: Ruben
authors.initials: R
authors.lastname: Pio
authors.forename: David
authors.initials: D
authors.lastname: Blanco
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000276:immunology; D060833:Cellular Microenvironment / Q000235:genetics* / Q000276:immunology; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004128:Dimethylnitrosamine; D005260:Female; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011014:Pneumonia / Q000139:chemically induced / Q000150:complications / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012822:Silicon Dioxide; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D016207:Cytokines; D016159:Tumor Suppressor Protein p53; D012822:Silicon Dioxide; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D004128:Dimethylnitrosamine
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