HMGB1 MEDIATES MINERAL FIBERS CARCINOGENESIS

Asbestos refers to a family of mineral fibers that includes crocidolite that is often considered the most oncogenic type. Asbestos causes ~ 2-3,000 malignant mesothelioma (MM) deaths/year in the US. The latency of 30-50 years from the time of exposure to tumor development could potentially allow time for interventions to block the mechanism/s that trigger asbestos-induced carcinogenesis, if they were known. Asbestos is cytotoxic to human mesothelial cells (HM), which appears counterintuitive for a carcinogen. How does asbestos cause malignant transformation of HM that leads to MM? It is a question that puzzles researchers for years. We found that asbestos-induced HM cell death is a regulated form of necrosis involving the release of HMGB1, which is critical to the carcinogenesis of asbestos. Asbestos-exposed HM activate PARP and translocate HMGB1 from the nucleus to the cytoplasm, and into the extracellular space. The release of HMGB1 induces macrophages to secrete TNF-α, which protects HM from asbestos-induced cell death and triggers a chronic inflammatory response; both favor HM transformation. These results were confirmed in animal models, i.e. mice and hamsters injected with asbestos. Recent data on erionite, another type of carcinogenic mineral fibers, showed the similar results. Erionite from North Dakota and erionite from mesothelioma villages in Cappadocia Turkey also induce HMGB1 release and TNF-α secretion as asbestos. Our findings identify the release of HMGB1 as a critical initial step in the carcinogenesis of mineral fibers and provide mechanistic links between mineral fiber-induced cell death, chronic inflammation and carcinogenesis. Moreover, HMGB1 serum levels in asbestos exposed human individuals were significantly higher than non-exposed controls, which suggest that HMGB1 could be a possible biomarker to identify individuals/cohorts exposed to asbestos. Chemopreventive approaches aimed at inhibiting the chronic inflammatory response initiated by HMGB1 may decrease the risk of MM among cohorts that have been exposed to carcinogenic mineral fibers.