Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma

Our plain-English summary of Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma, by M. Carbone, H. Yang (Clinical Cancer Research, 2012).

The study

• Authors: M. Carbone, H. Yang
• Journal: Clinical Cancer Research
• Published: 2012;18(3):598-604
• Cited by: 169 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is an aggressive malignancy related to asbestos and erionite exposure. AP-1 transcriptional activity and the NF-κB signaling pathway have been linked to mesothelial cell transformation and tumor progression. HGF and c-Met are highly expressed in mesotheliomas. Phosphoinositide 3-kinase, AKT, and the downstream mTOR are involved in cell growth and survival, and they are often found to be activated in mesothelioma. p16(INK4a) and p14(ARF) are frequently inactivated in human mesothelioma, and ∼50% of mesotheliomas contain the NF2 mutation. Molecular therapies aimed at interfering with these pathways have not improved the dismal prognosis of mesothelioma, except possibly for a small subset of patients who benefit from certain therapies. Recent studies have shown the importance of asbestos-induced inflammation in the initiation and growth of mesothelioma, and HMGB1 and Nalp3 inflammasome have been identified as key initiators of this process. Asbestos induces cell necrosis, causing the release of HMGB1, which in turn may activate Nalp3 inflammasome, a process that is enhanced by asbestos-induced production of reactive oxygen species. HMGB1 and Nalp3 induce proinflammatory responses and lead to interleukin-1β and TNF-α secretion and NF-κB activity, thereby promoting cell survival and tumor growth. Novel strategies that interfere with asbestos- and erionite-mediated inflammation might prevent or delay the onset of mesothelioma in high-risk cohorts, including genetically predisposed individuals, and/or inhibit tumor growth. The very recent discovery that germline BAP1 mutations cause a new cancer syndrome characterized by mesothelioma, uveal melanoma, and melanocytic tumors provides researchers with a novel target for prevention and early detection.

In plain English

This article was a review, not a new study. The authors summarized published laboratory, animal and clinical research on how asbestos and erionite may cause malignant mesothelioma. Erionite is a naturally occurring fibrous mineral that the authors described as more potent than asbestos in causing mesothelioma. The review described gene changes reported in mesothelioma, including NF2 mutations in about half of tumors. It noted that inherited BAP1 mutations had been linked to a new cancer syndrome with a very high risk of mesothelioma and uveal melanoma. It outlined a proposed process: asbestos kills mesothelial cells by necrosis, releasing a protein called HMGB1. HMGB1 may activate the Nalp3 inflammasome and drive inflammation that promotes the survival of damaged cells. The authors reported that targeted drug therapies had not improved average survival, although 5% to 10% of patients in several trials responded. They hypothesized that long-term aspirin might reduce mesothelioma in high-risk groups, and suggested HMGB1 might be a marker of exposure. The authors concluded that research on such anti-inflammatory strategies has the potential to reduce the effect of asbestos and erionite exposure.

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 laboratory, animal and clinical studies on molecular mechanisms of mesothelioma; no new data reported
• Who was studied: No study population of its own; the review drew on published cell, animal, epidemiological and clinical trial research
• Exposure: Asbestos (chrysotile and the amphiboles actinolite, tremolite, anthophyllite, amosite and crocidolite) and erionite, a naturally occurring fibrous mineral
• Main results:
  • The authors stated that erionite exposure is less widespread than asbestos exposure but more potent in causing mesothelioma (citing other studies)
  • The review reported that 50% of mesotheliomas contain NF2 gene mutations (the PubMed abstract gives approximately 50%)
  • The review reported that people with inherited (germline) BAP1 mutations have a novel cancer syndrome with a very high risk of mesothelioma and uveal melanoma (citing other studies)
  • Proposed mechanism: asbestos causes cell necrosis, releasing HMGB1, which may activate the Nalp3 inflammasome
  • Proposed mechanism: HMGB1 and Nalp3 lead to inflammatory signaling that promotes cell survival and tumor growth
  • Molecular therapies had not improved average survival of mesothelioma patients, although 5% to 10% of patients in several trials responded
  • The authors hypothesized that prolonged aspirin treatment may help reduce mesothelioma incidence in high-risk groups
  • The authors suggested, based on higher serum HMGB1 in asbestos-exposed people reported in a cited study, that HMGB1 may be a marker of exposure
• The authors' conclusion: The authors concluded that research on strategies targeting asbestos-induced inflammation has the potential to reduce the carcinogenic effect of asbestos and erionite exposure

Topics

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

Medical terms in this study, explained in our Lexicon: erionite, Carcinogenesis, Mesothelioma, Malignant Mesothelioma, Mesothelial Cells, Prognosis, Inflammation, High Mobility Group Box 1 (HMGB1).

Related studies

• Erionite and asbestos differently cause transformation of human mesothelial cells — P. Bertino, A. Marconi, et al. (2007)
• TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis — H. Yang, M. Bocchetta, et al. (2006)
• Erionite exposure in North Dakota and Turkish villages with mesothelioma — M. Carbone, Y.I. Baris, et al. (2011)
• Lung diseases due to environmental exposures to erionite and asbestos in Turkey — S. Emri, A. Demir, et al. (2002)
• Genetic predisposition to fiber carcinogenesis causes a mesothelioma epidemic in Turkey — A.U. Dogan, Y.I. Baris, et al. (2006)
• Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles — A. Valavanidis, T. Vlachogianni, et al. (2009)

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