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

Files
Oncogene Final Submission.pdf (11.41 MB)
Date
2015-06
Authors
Napolitano, Andrea
Pellegrini, Laura
Dey, A.
Larson, David
Tanji, Mika
Flores, Erin G.
Kendrick, Brian
Lapid, Danica
Powers, Amy
Kanodia, S.
Show 5 more
Contributor
Advisor
Department
Instructor
Depositor
Speaker
Researcher
Consultant
Interviewer
Annotator
Journal Title
Journal ISSN
Volume Title
Publisher
Nature Oncogene
Volume
Number/Issue
Starting Page
Ending Page
Alternative Title
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.
Description
Keywords
BAP1, BAP1 cancer syndrome, Germline, Mesothelioma, Asbestos, Dose, Inflammation, Macrophages, Polarization, M1, M2
Citation
URI
http://hdl.handle.net/10125/39964
Extent
26
Format
Geographic Location
Time Period
Related To
Table of Contents
Rights
Rights Holder
Local Contexts
Collections
University of Hawaii Cancer Center Faculty & Researcher Works
Email libraryada-l@lists.hawaii.edu if you need this content in ADA-compliant format.