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

Autor: Napolitano A; University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.; Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI, USA., Pellegrini L; University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA., Dey A; Department of Discovery Oncology, Genentech, South San Francisco, CA, USA., Larson D; University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA., Tanji M; University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA., Flores EG; University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA., Kendrick B; University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA., Lapid D; University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA., Powers A; University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA., Kanodia S; Department of Biomedical Sciences and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Pastorino S; University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA., Pass HI; Department of Cardiothoracic Surgery, New York University, New York, NY, USA., Dixit V; Department of Discovery Oncology, Genentech, South San Francisco, CA, USA., Yang H; University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA., Carbone M; University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2016 Apr 14; Vol. 35 (15), pp. 1996-2002. Date of Electronic Publication: 2015 Jun 29.
DOI: 10.1038/onc.2015.243
Abstrakt: Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with 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 with 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.
Competing Interests: M. Carbone has pending patent applications on BAP1 and provides consultation for mesothelioma expertise and diagnosis. The remaining authors declare no competing financial interests.
Databáze: MEDLINE
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