Exposure to
asbestos is causally associated with the development of
malignant mesothelioma, a
cancer of cells lining the internal body cavities.
Malignant mesothelioma is an aggressive
cancer resistant to all current
therapies. Once inhaled or ingested,
asbestos causes
inflammation in and around tissues that come in contact with these carcinogenic fibers. Recent studies suggest that
inflammation is a major contributing factor in the development of many types of
cancer, including
malignant mesothelioma. The NALP3/NLRP3
inflammasome, including the component ASC, is thought to be an important mediator of
inflammation in cells that sense extracellular insults, such as
asbestos, and activate a signaling cascade resulting in release of mature IL1β and recruitment of inflammatory cells. To determine if
inflammasome-mediated
inflammation contributes to
asbestos-induced
malignant mesothelioma, we chronically exposed Asc-deficient mice and wild-type littermates to
asbestos and evaluated differences in
tumor incidence and latency. The Asc-deficient mice showed significantly delayed
tumor onset and reduced
malignant mesothelioma incidence compared with wild-type animals. We also tested whether
inflammation-related release of IL1β contributes to
tumor development in an accelerated mouse model of
asbestos-induced
malignant mesothelioma. Nf2(+/-);Cdkn2a(+/-) mice exposed to
asbestos in the presence of
anakinra, an
IL1 receptor (IL1R) antagonist, showed a marked delay in the median time of
malignant mesothelioma onset compared with similarly exposed mice given vehicle control (33.1 weeks vs. 22.6 weeks, respectively). Collectively, these studies provide evidence for a link between
inflammation-related IL1β/IL1R signaling and the development of
asbestos-induced
malignant mesothelioma. Furthermore, these findings provide rationale for
chemoprevention strategies targeting IL1β/IL1R signaling in high-risk,
asbestos-exposed populations.
Cancer Prev Res; 9(5); 406-14. ©2016 AACR.