title: Differential Susceptibility of Human Pleural and Peritoneal Mesothelial Cells to Asbestos Exposure.
abstract: Malignant mesothelioma (MM) is an aggressive cancer of mesothelial cells of pleural and peritoneal cavities. In 85% of cases both pleural and peritoneal MM is caused by asbestos exposure. Although both are asbestos-induced cancers, the incidence of pleural MM is significantly higher (85%) than peritoneal MM (15%). It has been proposed that carcinogenesis is a result of asbestos-induced inflammation but it is not clear what contributes to the differences observed between incidences of these two cancers. We hypothesize that the observed differences in incidences of pleural and peritoneal MM are the result of differences in the direct response of these cell types to asbestos rather than to differences mediated by the in vivo microenvironment. To test this hypothesis we characterized cellular responses to asbestos in a controlled environment. We found significantly greater changes in genome-wide expression in response to asbestos exposure in pleural mesothelial cells as compared to peritoneal mesothelial cells. In particular, a greater response in many common genes (IL-8, ATF3, CXCL2, CXCL3, IL-6, GOS2) was seen in pleural mesothelial cells as compared to peritoneal mesothelial cells. Unique genes expressed in pleural mesothelial cells were mainly pro-inflammatory (G-CSF, IL-1β, IL-1α, GREM1) and have previously been shown to be involved in development of MM. Our results are consistent with the hypothesis that differences in incidences of pleural and peritoneal MM upon exposure to asbestos are the result of differences in mesothelial cell physiology that lead to differences in the inflammatory response, which leads to cancer.
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Medicine, University of Vermont, Burlington, Vermont, 05405.
authors.forename: Julie
authors.initials: J
authors.lastname: Dragon
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont, 05405.
authors.forename: Joyce
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont, 05405.
authors.forename: Maximilian
authors.initials: M
authors.lastname: MacPherson
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont, 05405.
authors.forename: Arti
authors.initials: A
authors.lastname: Shukla
mesh_terms: D000328:Adult; D000368:Aged; D017638:Asbestos, Crocidolite / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008654:Mesothelioma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D010534:Peritoneal Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D010997:Pleural Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D017423:Sequence Analysis, RNA
chemical_list: D017638:Asbestos, Crocidolite
keywords: ASBESTOS; INFLAMMATION; MASSIVELY PARALLEL SEQUENCING; MESOTHELIAL CELLS; MESOTHELIOMA; RNA-SEQ