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Kadariya Y , Menges CW , Talarchek J , Cai KQ , Klein-Szanto AJ , Pietrofesa RA , Christofidou-Solomidou M , Cheung M , Mossman BT , Shukla A , Testa JR
Inflammation-Related IL-1beta/IL-1R Signaling Promotes the Development of Asbestos-Induced Malignant Mesothelioma
Cancer Prev Res (Phila). 2016 Mar 2;9(5) :406-414
PMID: 26935421    PMCID: PMC4854753    URL: http://www.ncbi.nlm.nih.gov/pubmed/26935421
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Exposure to asbestos is causally associated with the development of malignant mesothelioma (MM), a cancer of cells lining the internal body cavities. MM 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 MM. 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 activates a signaling cascade resulting in release of mature IL-1beta and recruitment of inflammatory cells. To determine if inflammasome-mediated inflammation contributes to asbestos-induced MM, 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 MM incidence compared to wild-type animals. We also tested whether inflammation-related release of IL-1beta contributes to tumor development in an accelerated mouse model of asbestos-induced MM. Nf2+/-;Cdkn2a+/- mice exposed to asbestos in the presence of anakinra, an IL-1 receptor (IL-1R) antagonist, showed a marked delay in the median time of MM onset compared to similarly exposed mice given vehicle control (33.1 weeks versus 22.6 weeks, respectively). Collectively, these studies provide evidence for a link between inflammation-related IL-1beta/IL-1R signaling and the development of asbestos-induced MM. Furthermore, these findings provide rationale for chemoprevention strategies targeting IL-1beta/IL-1R signaling in high risk, asbestos-exposed populations.
Kadariya, Yuwaraj Menges, Craig W Talarchek, Jacqueline Cai, Kathy Q Klein-Szanto, Andres J P Pietrofesa, Ralph A Christofidou-Solomidou, Melpo Cheung, Mitchell Mossman, Brooke T Shukla, Arti Testa, Joseph R P30 CA006927/CA/NCI NIH HHS/United States P42 ES023720/ES/NIEHS NIH HHS/United States R01 CA190542/CA/NCI NIH HHS/United States R01 ES021110/ES/NIEHS NIH HHS/United States Cancer Prev Res (Phila). 2016 Mar 2. pii: canprevres.0347.2015.