4.3 Article

Silica-induced Chronic Inflammation Promotes Lung Carcinogenesis in the Context of an Immunosuppressive Microenvironment

Journal

NEOPLASIA
Volume 15, Issue 8, Pages 913-+

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1593/neo.13310

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Funding

  1. UTE project CIMA
  2. Spanish Ministries of Health/Economy and Competitivity [ISCIII: RTICC RD12/0036/0040, FIS-PI 04/2128, 10/00166]

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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-beta 1, 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.

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