New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas

Our plain-English summary of New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas, by B.T. Mossman, A. Shukla, N.H. Heintz, et al (The American Journal of Pathology, 2013).

The study

• Authors: B.T. Mossman, A. Shukla, N.H. Heintz, C.F. Verschraegen, A. Thomas, R. Hassan
• Journal: The American Journal of Pathology
• Published: 2013;182(4):1065-77
• Type of article: Review
• Cited by: 72 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a relatively rare but devastating tumor that is increasing worldwide. Yet, because of difficulties in early diagnosis and resistance to conventional therapies, MM remains a challenge for pathologists and clinicians to treat. In recent years, much has been revealed regarding the mechanisms of interactions of pathogenic fibers with mesothelial cells, crucial signaling pathways, and genetic and epigenetic events that may occur during the pathogenesis of these unusual, pleiomorphic tumors. These observations support a scenario whereby mesothelial cells undergo a series of chronic injury, inflammation, and proliferation in the long latency period of MM development that may be perpetuated by durable fibers, the tumor microenvironment, and inflammatory stimuli. One culprit in sustained inflammation is the activated inflammasome, a component of macrophages or mesothelial cells that leads to production of chemotactic, growth-promoting, and angiogenic cytokines. This information has been vital to designing novel therapeutic approaches for patients with MM that focus on immunotherapy, targeting growth factor receptors and pathways, overcoming resistance to apoptosis, and modifying epigenetic changes.

Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

In plain English

This article was a review, not a new study. The authors brought together published laboratory, animal and clinical research on malignant mesothelioma, a cancer that arises most often from the lining of the chest (pleura) or abdomen (peritoneum) and occasionally the lining around the heart. They described asbestos fibers, listing crocidolite, amosite, tremolite, anthophyllite and antigorite as amphiboles and chrysotile as a serpentine fiber. They also mentioned erionite and Libby amphibole. Citing other work, the review reported that 70% to 80% of mesotheliomas are associated with occupational asbestos exposure, that fewer than 5% of asbestos workers develop the disease, and that 20% to 25% of people with mesothelioma have no documented exposure to asbestos or other fibers. It summarized research on how fibers may cause repeated injury and inflammation, including activation of the NLRP3 inflammasome, and on gene changes such as loss of NF2. It also summarized treatment studies on surgery, radiation, chemotherapy such as cisplatin plus pemetrexed, and experimental drugs and immunotherapies. The authors concluded that mesotheliomas are a complex, varied group of tumors.

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 of malignant mesothelioma
• Who was studied: No new participants. The review drew on published work using patient specimens, human mesothelioma cell lines, animal models and clinical trials.
• Exposure: Asbestos, which the article describes as needle-like amphiboles (crocidolite, amosite, tremolite, anthophyllite and antigorite, as the article lists them) or curly serpentine (chrysotile) fibers. The non-asbestos fibers erionite and Libby amphibole were also discussed.
• Main results:
  • The review reported (citing other studies) that 70% to 80% of malignant mesotheliomas are associated with occupational asbestos exposure, and that fewer than 5% of asbestos workers develop mesothelioma.
  • The review stated that 20% to 25% of individuals with mesothelioma have no documented exposure to asbestos or other fibers.
  • The review stated that no specific associations between exposure to different fiber types and distinct mesothelioma tumor subtypes have been reported.
  • Citing other work, the review reported that inactivation of the NF2 gene is observed in 40% to 50% of mesotheliomas.
  • The review described studies showing that inhaled chrysotile fibers, and crocidolite asbestos in laboratory (in vitro) experiments, activate the NLRP3 inflammasome, which is required for release of the inflammatory signal IL-1b in human macrophages and monocytes.
  • In the published trial comparing cisplatin plus pemetrexed with cisplatin alone, the combination was associated with response rates of 41.3% versus 16.7% and median overall survival of 12.1 versus 9.3 months (HR 0.77).
  • In the Mesothelioma and Radical Surgery trial, patients assigned to extrapleural pneumonectomy (n=24) had a median overall survival of 14.4 months, compared with 19.5 months for the non-EPP group (n=26).
  • The review reported that EGFR is overexpressed in 44% to 97% of mesothelioma specimens. It also reported that the EGFR inhibitors gefitinib and erlotinib showed no significant clinical activity in phase II trials.
  • A phase III placebo-controlled trial of vorinostat in previously treated advanced mesothelioma did not show improved overall survival: median 31 weeks with vorinostat versus 27 weeks with placebo.
• The authors' conclusion: The authors concluded that the data suggest mesotheliomas are a complex, pleiomorphic group of tumors whose phenotypes are governed by cytokines and growth factors. They also concluded that new treatment approaches have been based on mechanisms important in how mesothelioma develops.
• Limitations the authors state:
  • The authors noted that evidence on surgery comes largely from observational studies, because randomized trials are lacking.
  • The authors noted that proposed new diagnostic tests based on epigenetic profiles or microRNAs need further substantiation.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Mesothelial Cells, Inflammation, Latency, Tumor Microenvironment, Macrophage, Cytokine, Immunotherapy.

Related studies

• New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma — T. Patel (2014)
• New insight into the molecular mechanisms of the biological effects of DNA minor groove binders — X. Zhang, S.C. Zhang, et al. (2011)
• Effects of Chrysotile Exposure in Human Bronchial Epithelial Cells: Insights into the Pathogenic Mechanisms of Asbestos-Related Diseases — G.R. Gulino, M. Polimeni, et al. (2016)
• Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies — A. Bononi, A. Napolitano, et al. (2015)
• Mechanisms in the pathogenesis of asbestosis and silicosis — B.T. Mossman, A. Churg (1998)
• Iron from a geochemical viewpoint. Understanding toxicity/pathogenicity mechanisms in iron-bearing minerals with a special attention to mineral fibers — A.F. Gualtieri, G.B. Andreozzi, et al. (2019)

Browse more research in The American Journal of Pathology, or return to medical research.