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HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma. 2023

Joelle S Suarez, and Flavia Novelli, and Keisuke Goto, and Michiko Ehara, and Mika Steele, and Jin-Hee Kim, and Alicia A Zolondick, and Jiaming Xue, and Ronghui Xu, and Mai Saito, and Sandra Pastorino, and Michael Minaai, and Yasutaka Takanishi, and Mitsuru Emi, and Ian Pagano, and Andrew Wakeham, and Thorsten Berger, and Harvey I Pass, and Giovanni Gaudino, and Tak W Mak, and Michele Carbone, and Haining Yang
Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96813.

Asbestos is the main cause of malignant mesothelioma. Previous studies have linked asbestos-induced mesothelioma to the release of HMGB1 from the nucleus to the cytoplasm, and from the cytoplasm to the extracellular space. In the cytoplasm, HMGB1 induces autophagy impairing asbestos-induced cell death. Extracellularly, HMGB1 stimulates the secretion of TNFα. Jointly, these two cytokines kick-start a chronic inflammatory process that over time promotes mesothelioma development. Whether the main source of extracellular HMGB1 were the mesothelial cells, the inflammatory cells, or both was unsolved. This information is critical to identify the targets and design preventive/therapeutic strategies to interfere with asbestos-induced mesothelioma. To address this issue, we developed the conditional mesothelial HMGB1-knockout (Hmgb1ΔpMeso) and the conditional myelomonocytic-lineage HMGB1-knockout (Hmgb1ΔMylc) mouse models. We establish here that HMGB1 is mainly produced and released by the mesothelial cells during the early phases of inflammation following asbestos exposure. The release of HMGB1 from mesothelial cells leads to atypical mesothelial hyperplasia, and in some animals, this evolves over the years into mesothelioma. We found that Hmgb1ΔpMeso, whose mesothelial cells cannot produce HMGB1, show a greatly reduced inflammatory response to asbestos, and their mesothelial cells express and secrete significantly reduced levels of TNFα. Moreover, the tissue microenvironment in areas of asbestos deposits displays an increased fraction of M1-polarized macrophages compared to M2 macrophages. Supporting the biological significance of these findings, Hmgb1ΔpMeso mice showed a delayed and reduced incidence of mesothelioma and an increased mesothelioma-specific survival. Altogether, our study provides a biological explanation for HMGB1 as a driver of asbestos-induced mesothelioma.

UI MeSH Term Description Entries
D007249 Inflammation A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. Innate Inflammatory Response,Inflammations,Inflammatory Response, Innate,Innate Inflammatory Responses
D008654 Mesothelioma A tumor derived from mesothelial tissue (peritoneum, pleura, pericardium). It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos. (Dorland, 27th ed) Mesotheliomas
D000086002 Mesothelioma, Malignant A type of mesothelioma with a tendency to metastasize. Most tumors originate from either the PLEURA or PERITONEUM, tumors may also originate in the PERICARDIUM or testicular tissue. It is associated with ASBESTOS exposure. Somatic mutations identified in WT1, BCL10, CDKN2A, NF2, and BAP1 genes are associated with the malignancy. OMIM: 156240. Malignant Mesothelioma,Malignant Pleural Mesothelioma,Mesothelioma, Malignant Pleural,Malignant Mesotheliomas,Malignant Pleural Mesotheliomas,Mesotheliomas, Malignant,Mesotheliomas, Malignant Pleural,Pleural Mesothelioma, Malignant,Pleural Mesotheliomas, Malignant
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001194 Asbestos Asbestos. Fibrous incombustible mineral composed of magnesium and calcium silicates with or without other elements. It is relatively inert chemically and used in thermal insulation and fireproofing. Inhalation of dust causes asbestosis and later lung and gastrointestinal neoplasms.
D014409 Tumor Necrosis Factor-alpha Serum glycoprotein produced by activated MACROPHAGES and other mammalian MONONUCLEAR LEUKOCYTES. It has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. Also known as TNF-alpha, it is only 30% homologous to TNF-beta (LYMPHOTOXIN), but they share TNF RECEPTORS. Cachectin,TNF-alpha,Tumor Necrosis Factor Ligand Superfamily Member 2,Cachectin-Tumor Necrosis Factor,TNF Superfamily, Member 2,TNFalpha,Tumor Necrosis Factor,Cachectin Tumor Necrosis Factor,Tumor Necrosis Factor alpha
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D059016 Tumor Microenvironment The milieu surrounding neoplasms consisting of cells, vessels, soluble factors, and molecules, that can influence and be influenced by, the neoplasm's growth. Cancer Microenvironment,Cancer Microenvironments,Microenvironment, Cancer,Microenvironment, Tumor,Microenvironments, Cancer,Microenvironments, Tumor,Tumor Microenvironments
D024243 HMGB1 Protein A 24-kDa HMGB protein that binds to and distorts the minor grove of DNA. HMG1,Amphoterin,Box Protein 1, High Mobility Group,FM1 Gene Product,HMG 1 Protein,HMG-1 Protein,HMGB1,Heparin-Binding Protein p30,Heparin Binding Protein p30,p30, Heparin-Binding Protein

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