Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma

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dc.contributor.author Napolitano, Andrea
dc.contributor.author Pellegrini, Laura
dc.contributor.author Dey, A.
dc.contributor.author Larson, David
dc.contributor.author Tanji, Mika
dc.contributor.author Flores, Erin G.
dc.contributor.author Kendrick, Brian
dc.contributor.author Lapid, Danica
dc.contributor.author Powers, Amy
dc.contributor.author Kanodia, S.
dc.contributor.author Pastorino, Sandra
dc.contributor.author Pass, H.I.
dc.contributor.author Dixit, V.
dc.contributor.author Yang, Haining
dc.contributor.author Cabone, Michele
dc.date.accessioned 2016-03-10T03:04:36Z
dc.date.available 2016-03-10T03:04:36Z
dc.date.issued 2015-06
dc.description.abstract Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated to professional exposure to asbestos. However, to date we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure. Using a BAP1+/- mouse model, we found that, compared to their wild type littermates, BAP1+/- mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1+/- mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild type mice. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.
dc.format.extent 26
dc.identifier.doi 10.1038/onc.2015.243
dc.identifier.uri http://hdl.handle.net/10125/39964
dc.language.iso en-US
dc.publisher Nature Oncogene
dc.relation.uri http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2015243a.html
dc.subject BAP1
dc.subject BAP1 cancer syndrome
dc.subject Germline
dc.subject Mesothelioma
dc.subject Asbestos
dc.subject Dose
dc.subject Inflammation
dc.subject Macrophages
dc.subject Polarization
dc.subject M1
dc.subject M2
dc.title Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma
dc.type Article
dc.type.dcmi Text
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