Abstract 5919: The significant role of HMGB1 in mesothelial cells in contributing to the mesothelioma development induced by asbestos

Abstract

Abstract Diffuse Malignant mesothelioma is a very aggressive cancer that is related to asbestos exposure. We found previously that following asbestos deposition in the pleura and in the peritoneum, mesothelial cells release HMGB1 that attract granulocytes and macrophages that, in turn, secrete HMGB1. It was unknown whether the primary source of HMGB1 that drives the inflammatory process caused by asbestos, which may ensue in mesothelioma, derives from the mesothelial cells exposed to asbestos or from the granulocytes and macrophages. To study separately the contribution of mesothelial cells and of the inflammatory cells to HMGB1 secretion that drives mesothelioma development, we used two tissue-specific HMGB1 knockout mouse models: (1) An inducible mesothelial conditional HMGB1 knockout (HMGB1ΔpMeso) mouse model, and (2) a constitutive myelomonocytic-lineage knock out (HMGB1ΔMylc) mouse model. To investigate the role of HMGB1 in asbestos induced carcinogenesis in vivo, we conducted both short-term and long-term experiments in HMGB1ΔpMeso mice and in HMGB1ΔMylc mice. For the Short-term experiment, we observed that one week following the completion of the 10-weekly crocidolite i.p. injections, all the mice in experimental and control groups showed inflammation with multiple granulomas around asbestos deposits in the various tissues and organs present in the abdomen, and diffuse mesothelial hyperplasia. However, the granulomas in HMGB1ΔpMeso mice were significantly smaller compared to those found in the control WT mice. TNFα IHC stain was minimal to non-detectable in the granulomas and areas of mesothelial hyperplasia of HMGB1ΔpMeso mice, compared to a strong TNFα staining in both HMGB1ΔMylc and WT mice. For the Long-term experiment, we observed that the incidence of mesothelioma was significantly lower in HMGB1ΔpMeso mice compared with the 3 control groups including WT mice, HMGB1F/F mice and Wt1ERT2Cre/+ control mice. Moreover, HMGB1ΔpMeso mice had a significantly longer mesothelioma-specific survival compared to all three controls. Histologically, the HMGB1ΔpMeso mesotheliomas were smaller and grew largely over the surface rather than infiltrating the abdominal organs, compared to the mesotheliomas that developed in the three control groups. In summary, our findings underscore the role of HMGB1 in asbestos pathogenesis, including asbestos induced chronic inflammation and mesothelioma. Moreover, our findings elucidated the mechanisms responsible for asbestos induced inflammation and asbestos carcinogenesis, and the causal link between HMGB1, TNFα secretion and mesothelioma. Our results point to the HMGB1 secreted by mesothelial cells as the culprit and thus the ideal target to prevent the growth of mesothelioma upon asbestos exposure and during the early phases of mesothelioma growth. Citation Format: Joelle S. Suarez, Giovanni Gaudino, Tak W. Mak, Michele Carbone, Haining Yang. The significant role of HMGB1 in mesothelial cells in contributing to the mesothelioma development induced by asbestos [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5919.