title: Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma.
abstract: 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.
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Napolitano
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Pellegrini
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dey
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
authors.forename: D
authors.initials: D
authors.lastname: Larson
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tanji
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
authors.forename: E G
authors.initials: EG
authors.lastname: Flores
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kendrick
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
authors.forename: D
authors.initials: D
authors.lastname: Lapid
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
authors.forename: A
authors.initials: A
authors.lastname: Powers
authors.affiliation: Department of Biomedical Sciences and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kanodia
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pastorino
authors.affiliation: Department of Cardiothoracic Surgery, New York University, New York, NY, USA.
authors.forename: H I
authors.initials: HI
authors.lastname: Pass
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, CA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Dixit
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Carbone
mesh_terms: D000818:Animals; D017638:Asbestos, Crocidolite / Q000008:administration & dosage / Q000633:toxicity*; D001202:Ascitic Fluid / Q000737:chemistry; D018925:Chemokines / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006579:Heterozygote; D007962:Leukocytes / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000145:classification / Q000502:physiology; D008297:Male; D008654:Mesothelioma / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D019016:Mineral Fibers / Q000633:toxicity; D010534:Peritoneal Neoplasms / Q000209:etiology* / Q000235:genetics; D010538:Peritonitis / Q000209:etiology / Q000235:genetics; D011897:Random Allocation; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D043222:Ubiquitin Thiolesterase / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
chemical_list: C575444:BAP1 protein, mouse; D018925:Chemokines; D016207:Cytokines; D019016:Mineral Fibers; D025521:Tumor Suppressor Proteins; D017638:Asbestos, Crocidolite; D043222:Ubiquitin Thiolesterase