Asbestos-induced chronic inflammation in malignant pleural mesothelioma and related therapeutic approaches-a narrative review

Our plain-English summary of Asbestos-induced chronic inflammation in malignant pleural mesothelioma and related therapeutic approaches-a narrative review, by A.A. Zolondick, G. Gaudino, J. Xue, et al (Precision Cancer Medicine, 2021).

The study

• Authors: A.A. Zolondick, G. Gaudino, J. Xue, H.I. Pass, M. Carbone, H. Yang
• Journal: Precision Cancer Medicine
• Published: 2021;4
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objective: The aim of this review is addressing the mechanisms of asbestos carcinogenesis, including chronic inflammation and autophagy-mediated cell survival, and propose potential innovative therapeutic targets to prevent mesothelioma development or improve drug efficacy by reducing inflammation and autophagy.

Background: Diffuse malignant pleural mesothelioma is an aggressive cancer predominantly related to chronic inflammation caused by asbestos exposure. Millions of individuals have been exposed to asbestos or to other carcinogenic mineral fibers occupationally or environmentally, resulting in an increased risk of developing mesothelioma. Overall patient survival rates are notably low (about 8-14 months from the time of diagnosis) and mesothelioma is resistant to existing therapies. Additionally, individuals carrying inactivating germline mutations in the BRCA-associated protein 1 (BAP1) gene and other genes are predisposed to developing cancers, prevalently mesothelioma. Their risk of developing mesothelioma further increases upon exposure to asbestos. Recent studies have revealed the mechanisms and the role of inflammation in asbestos carcinogenesis. Biomarkers for asbestos exposure and malignant mesothelioma have also been identified. These findings are leading to the development of novel therapeutic approaches to prevent or delay the growth of mesothelioma.

Methods: Review of full length manuscripts published in English from January 1980 to February 2021 gathered from PubMed.gov from the National Center of Biotechnology Information and the National Library of Medicine were used to inform this review.

Conclusion: Key regulators of chronic inflammation mediate asbestos-driven mesothelial cell transformation and survival through autophagic pathways. Recent studies have elucidated some of the key mechanisms involved in asbestos-induced chronic inflammation, which are largely driven by extracellular high mobility group box 1 (HMGB1). Upon asbestos exposure, mesothelial cells release HMGB1 from the nucleus to the cytoplasm and extracellular space, where HMGB1 initiates an inflammatory response. HMGB1 translocation and release also activates autophagy and other pro-survival mechanisms, which promotes mesothelioma development. HMGB1 is currently being investigated as a biomarker to detect asbestos exposure and to detect mesothelioma development in its early stage when therapy is more effective. In parallel, several approaches inhibiting HMGB1 activities have been studied and have shown promising results. Moreover, additional cytokines, such as IL-1β and TNF-α are being targeted to interfere with the inflammatory process that drives mesothelioma growth. Developing early detection methods and novel therapeutic strategies is crucial to prolong overall survival of patients with mesothelioma. Novel therapies targeting regulators of asbestos-induced inflammation to reduce mesothelioma growth may lead to clinical advancements to benefit patients with mesothelioma.

In plain English

This article was a narrative review, not a new study. The authors drew on English-language papers found through PubMed and published between January 1980 and February 2021. They used them to describe how asbestos may lead to malignant pleural mesothelioma through chronic inflammation, and to discuss possible treatments. The studies they reviewed reported that asbestos kills human mesothelial cells mostly by necrosis, and that the dying cells release a protein called HMGB1 that sets off inflammation. Reviewed work also reported that HMGB1 moving out of the cell nucleus switches on autophagy, a survival process. Other reviewed work reported higher blood HMGB1 levels in asbestos-exposed people, and that about 30% of carriers of inherited BAP1 mutations have developed diffuse malignant mesothelioma. The candidate treatments described included ethyl pyruvate, aspirin, BoxA, anti-HMGB1 antibodies and Anakinra. They had been tested in cell cultures and mice, where some reduced tumor growth. The authors concluded that blocking HMGB1 had shown promising results in laboratory and mouse studies, and they expressed hope that such therapies would benefit patients.

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 literature
• Who was studied: No new patients or subjects were studied. The review drew on published English-language manuscripts from PubMed, January 1980 to February 2021, including cell, mouse and human studies by other researchers (several by the authors' own group).
• Exposure: Asbestos in general. The review describes six fiber types (chrysotile, amosite, crocidolite, anthophyllite, tremolite, actinolite) and discusses chrysotile, crocidolite and amosite in particular. It also discusses inherited mutations in BAP1 and other genes as factors affecting susceptibility.
• Main results:
  • Studies reviewed reported that asbestos kills human mesothelial cells mostly by necrosis, and that the dying cells release HMGB1, which starts inflammation.
  • The review cites experimental evidence that prolonged, continuous chrysotile exposure also transformed human mesothelial cells in the laboratory, even though chrysotile is described as less carcinogenic than crocidolite.
  • A cited study by Xue et al. reported that asbestos moved HMGB1 from the nucleus to the cytoplasm in human mesothelial cells, activating autophagy, which the authors describe as letting cells escape death despite DNA damage.
  • In a cited mouse study, IL-1β secretion after asbestos exposure was lower in NLRP3-deficient mice than in normal mice, but mesothelioma incidence did not differ significantly between the two groups.
  • Cited studies reported elevated serum HMGB1 in asbestos-exposed individuals, with further increases during mesothelioma development. The authors describe HMGB1 as a potential biomarker.
  • The review cites that about 30% of carriers of germline BAP1 mutations have developed diffuse malignant mesothelioma.
  • According to the review, overall survival for patients with sporadic mesothelioma is about 8 to 14 months from diagnosis, compared with a median survival of 5 to 7 years for patients carrying germline mutations.
  • In cited mouse xenograft studies, ethyl pyruvate treatment produced smaller tumors and lower serum HMGB1 than in untreated mice.
  • In a cited comparison in mouse mesothelioma xenografts, aspirin and BoxA both reduced tumor growth, and BoxA-treated mice survived longer than aspirin-treated mice.
  • In cited studies, Anakinra (an IL-1 receptor antagonist) increased survival of genetically modified Nf2+/− and Cdkna2+/− mice exposed to asbestos.
• The authors' conclusion: The authors concluded that chronic inflammation caused by asbestos drives mesothelial cell transformation, largely through extracellular HMGB1. They stated that targeting HMGB1 has shown promising results in cell and mouse studies, and they hoped such therapies would bring clinical improvements for patients.

Topics

Medical terms in this study, explained in our Lexicon: Chronic Inflammation, Pleural Mesothelioma, Carcinogenesis, Mesothelioma, Inflammation, Asbestos Exposure, Carcinogenic, Mineral Fiber.

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• Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation — H. Yang, Z. Rivera, et al. (2010)
• HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma — J.S. Suarez, F. Novelli, et al. (2023)
• Inflammation-Related IL1β/IL1R Signaling Promotes the Development of Asbestos-Induced Malignant Mesothelioma — Y. Kadariya, C.W. Menges, et al. (2016)
• Targeting microRNA to improve diagnostic and therapeutic approaches for malignant mesothelioma — K.A. Birnie, C.M. Prêle, et al. (2017)
• Management of malignant pleural mesothelioma-part 2: therapeutic approaches : Consensus of the Austrian Mesothelioma Interest Group (AMIG) — M.A. Hoda, T. Klikovits, et al. (2016)

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