Abstract 842: The NALP3 inflammasome and IL-1â signaling link asbestos-induced inflammation with the development of malignant mesothelioma

Abstract

Abstract Exposure to asbestos is causally associated with the development of malignant mesothelioma (MM), a cancer of cells lining the internal body cavity. MM is an aggressive cancer that is 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 inflammasome, including the component ASC, is an important mediator of inflammation that senses extracellular insults, such as infection or asbestos, and activates a signaling cascade resulting in release of mature IL-1â and recruitment of inflammatory cells. To determine if inflammasome-mediated inflammation contributes to asbestos-induced MM, we chronically exposed Asc-deficient mice to asbestos and evaluated tumor incidence, latency and overall survival. Asc-deficient mice showed a significant delay in tumor onset compared to wild-type animals, suggesting that the NALP3 inflammasome plays a role in MM carcinogenesis. We also tested whether inflammation-related release of IL-1â promotes tumor development in an accelerated mouse model of asbestos-induced MM. Nf2+/-;Cdkn2a+/- mice exposed to asbestos in the presence of the IL-1â antagonist, anakinra, showed a 50% longer disease-free survival than in similarly exposed mice given vehicle control, consistent with IL-1â signaling contributing significantly to MM development. Collectively, these studies provide evidence for a link between asbestos-associated inflammation/IL-1â signaling and the development of MM; furthermore, these findings provide rationale for chemoprevention strategies targeting inflammation-related IL-1â signaling in high risk, asbestos-exposed populations. Citation Format: Yuwaraj Kadariya, Craig W. Menges, Jacqueline Talarchek, Qi Cai, Andres J. Klein-Szanto, Ralph A. Pietrofesa, Melpo Christofidou-Solomidou, Brooke T. Mossman, Arti Shukla, Joseph R. Testa. The NALP3 inflammasome and IL-1â signaling link asbestos-induced inflammation with the development of malignant mesothelioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 842.