Chronic Inflammation in Malignant Mesothelioma Pathogenesis: Focus on HMGB1 Isoforms and Germline BAP1 Mutations

Abstract

Malignant mesothelioma (MM) is an aggressive cancer arising from the mesothelial cells forming the lining of the pleural, pericardial, and peritoneal cavities. Prolonged exposure to carcinogenic mineral fibers, such as asbestos, is the most important risk factor for MM development. Mechanistically, asbestos-induced chronic inflammation is considered a crucial event in MM pathogenesis. High Mobility Group Box 1 (HMGB1) is a pro-inflammatory molecule previously identified as mediator of both asbestos-induced carcinogenesis and MM progression. Here, we show that total HMGB1 levels can reliably distinguish asbestos-exposed individuals and MM patients from healthy controls. Moreover, a specific HMGB1 isoform|hyper-acetylated HMGB1|is significantly increased in MM patients compared to asbestos-exposed individuals and healthy controls. Finally, total and hyper-acetylated HMGB1 can also help differentiating MM patients from patients with pleural effusions due to other causes. Our results suggest that hyper-acetylated HMGB1 might represent a promising novel biomarker for early diagnosis of MM. Continuing our effort to refine the identification of individuals at risk of developing MM, we sought to investigate the role of asbestos exposure in presence of germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1), which have been recently reported as predisposing events to MM and several other cancers. However, in individuals with germline BAP1 mutations that developed MM, occupational exposure to asbestos is not usually reported. Here, using a genetically engineered murine model, we discovered that minimal exposure to asbestos causes a deregulated chronic inammatory response and increased risk of MM in presence of germline BAP1 heterozygosity, suggesting that doses of asbestos considered not harmful for the general population might cause the disease in genetically predisposed individuals.