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.authorNapolitano, Andrea
dc.contributor.authorPellegrini, Laura
dc.contributor.authorDey, A.
dc.contributor.authorLarson, David
dc.contributor.authorTanji, Mika
dc.contributor.authorFlores, Erin G.
dc.contributor.authorKendrick, Brian
dc.contributor.authorLapid, Danica
dc.contributor.authorPowers, Amy
dc.contributor.authorKanodia, S.
dc.contributor.authorPastorino, Sandra
dc.contributor.authorPass, H.I.
dc.contributor.authorDixit, V.
dc.contributor.authorYang, Haining
dc.contributor.authorCabone, Michele
dc.date.accessioned2016-03-10T03:04:36Z
dc.date.available2016-03-10T03:04:36Z
dc.date.issued2015-06
dc.description.abstractGermline 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.extent26
dc.identifier.doi10.1038/onc.2015.243
dc.identifier.urihttp://hdl.handle.net/10125/39964
dc.language.isoen-US
dc.publisherNature Oncogene
dc.relation.urihttp://www.nature.com/onc/journal/vaop/ncurrent/full/onc2015243a.html
dc.subjectBAP1
dc.subjectBAP1 cancer syndrome
dc.subjectGermline
dc.subjectMesothelioma
dc.subjectAsbestos
dc.subjectDose
dc.subjectInflammation
dc.subjectMacrophages
dc.subjectPolarization
dc.subjectM1
dc.subjectM2
dc.titleMinimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma
dc.typeArticle
dc.type.dcmiText

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