Preventive and therapeutic opportunities: targeting BAP1 and/or HMGB1 pathways to diminish the burden of mesothelioma

Our plain-English summary of Preventive and therapeutic opportunities: targeting BAP1 and/or HMGB1 pathways to diminish the burden of mesothelioma, by M. Carbone, M. Minaai, Y. Takinishi, et al (Journal of Translational Medicine, 2023).

The study

• Authors: M. Carbone, M. Minaai, Y. Takinishi, I. Pagano, H. Yang
• Journal: Journal of Translational Medicine
• Published: 2023;21(1):749
• Type of article: Review
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is a cancer typically caused by asbestos. Mechanistically, asbestos carcinogenesis has been linked to the asbestos-induced release of HMGB1 from the nucleus to the cytoplasm, where HMGB1 promotes autophagy and cell survival, and to the extracellular space where HMGB1 promotes chronic inflammation and mesothelioma growth. Targeting HMGB1 inhibited asbestos carcinogenesis and the growth of mesothelioma. It is hoped that targeting HMGB1 will be a novel therapeutic strategy that benefits mesothelioma patients. Severe restrictions and/or a complete ban on the use of asbestos were introduced in the 80 and early 90s in the Western world. These measures have proven effective as the incidence of mesothelioma/per 100,000 persons is decreasing in these countries. However, the overall number of mesotheliomas in the Western world has not significantly decreased. There are several reasons for that which are discussed here: (1) the presence of asbestos in old constructions; (2) the development of rural areas containing asbestos or other carcinogenic mineral fibers in the terrain; (3) the discovery of an increasing fraction of mesotheliomas caused by germline genetic mutations of BAP1 and other tumor suppressor genes; (4) mesotheliomas caused by radiation therapy; (5) the overall increase in the population and of the fraction of older people who are much more susceptible to develop all types of cancers, including mesothelioma. In summary, the epidemiology of mesothelioma is changing, the ban on asbestos worked, there are opportunities to help mesothelioma patients especially those who develop in a background of germline mutations and there is the opportunity to prevent a mesothelioma epidemic in the developing world, where the use of asbestos is increasing exponentially. We hope that restrictive measures similar to those introduced in the Western world will soon be introduced in developing countries to prevent a mesothelioma epidemic.

© 2023. BioMed Central Ltd., part of Springer Nature.

In plain English

This article was a review, not a new study. The authors summarized published research on the causes, biology and diagnosis of mesothelioma. They wrote that after asbestos was banned or severely restricted in the USA, Western Europe and Australia in the 80s, mesothelioma incidence declined, but only in males. They also wrote that the total number of cases had not declined significantly, at least in the USA, as the population grew. They described other sources of mesothelioma: asbestos in old buildings, fibers that occur naturally in the environment such as erionite and antigorite, past radiation therapy, and inherited (germline) gene mutations. An estimated 12–16% of mesotheliomas are linked to germline mutations, most commonly in the BAP1 gene. They reviewed evidence that asbestos promotes mesothelioma through chronic inflammation driven by the release of a protein called HMGB1. Drugs blocking HMGB1 slowed mesothelioma growth in mice and in human mesothelioma cells grown in the laboratory. Mesotheliomas in BAP1 carriers were reported to have a median survival of 6–7 years. The authors concluded that the bans worked. They suggested that similar measures be introduced in developing countries.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published research; no new datasets were generated or analyzed
• Who was studied: No new study population. The review drew on published studies of mesothelioma, mainly in industrialized countries (USA, Australia, Western Europe). The authors also referred to their own ongoing follow-up of 98 families carrying BAP1 mutations in the US and abroad.
• Exposure: Asbestos (including crocidolite and chrysotile, as mentioned in cited studies), naturally occurring fibers such as erionite and antigorite, asbestos in old constructions, radiation therapy for earlier cancers, and germline mutations of BAP1 and other tumor suppressor genes (such as TP53, BRCA1, BRCA2, BLM)
• Main results:
  • In industrialized countries that banned or restricted asbestos, the review reported a decline in mesothelioma incidence, seen only in males.
  • While the incidence per 100,000 persons is decreasing, the overall number of mesotheliomas has not declined significantly, at least in the USA, as the total population is increasing.
  • Citing other studies, the review stated that 12–16% of mesotheliomas are linked to germline mutations, with BAP1 the most common.
  • Citing earlier studies, the review stated that drugs inhibiting HMGB1 directly or indirectly (such as BoxA, monoclonal antibodies, aspirin, ethyl pyruvate) inhibited mesothelioma growth in mice and in human mesothelioma cell lines in tissue culture. These were not results in patients.
  • Mesotheliomas in patients carrying germline BAP1 mutations were described as mostly less aggressive, with a median survival of 6–7 years (from cited studies).
  • In the authors' follow-up of BAP1 mutant families, affected family members eventually developed cancer, about 30% of them mesothelioma.
  • The review stated that over 60% of sporadic (not inherited) mesotheliomas carry biallelic inactivating BAP1 mutations.
  • For developing countries, where asbestos use is increasing, the authors suggested introducing restrictive measures similar to those in the Western world.
• The authors' conclusion: The authors concluded that asbestos bans and restrictive measures in the Western world have been effective in reducing mesothelioma incidence. They noted that asbestos-induced mesotheliomas and those in BAP1 carriers share a mechanism involving extracellular HMGB1 release, which they hoped could be targeted to help all mesothelioma patients.
• Limitations the authors state:
  • The authors stated that studies of mesothelioma incidence in developing countries are difficult to interpret and biased by shorter life expectancy and imprecise diagnosis.
  • The authors stated that the relevance of the asbestos and SV40 virus interaction to human mesothelioma remains to be demonstrated, because supporting epidemiological data are absent.
  • The authors noted discrepancies in the literature on cancer incidence in BAP1 carriers: around 80% in some articles versus close to 100% in their own reports.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, High Mobility Group Box 1 (HMGB1), Mesothelioma, Carcinogenesis, Chronic Inflammation, Carcinogenic, Mineral Fiber, Discovery.

Related studies

• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)
• HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma — L. Pellegrini, J. Xue, et al. (2017)
• HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma — J.S. Suarez, F. Novelli, et al. (2023)
• HMGB1 as a Potential Biomarker and Therapeutic Target for Malignant Mesothelioma — Y. Wang, Z. Jiang, et al. (2019)
• Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma — S. Jube, Z.S. Rivera, et al. (2012)
• HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients — A. Napolitano, D.J. Antoine, et al. (2016)

Browse more research in Journal of Translational Medicine, or return to medical research.