Molecular pathogenesis of malignant mesothelioma

Our plain-English summary of Molecular pathogenesis of malignant mesothelioma, by P.A. Rascoe, D. Jupiter, X. Cao, et al (Expert Reviews in Molecular Medicine, 2012).

The study

• Authors: P.A. Rascoe, D. Jupiter, X. Cao, J.E. Littlejohn, W.R. Smythe
• Journal: Expert Reviews in Molecular Medicine
• Published: 2012;14:e12
• Type of article: Review
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma is a rare, highly aggressive cancer arising from mesothelial cells that line the pleural cavities. Approximately 80% of mesothelioma cases can be directly attributed to asbestos exposure. Additional suspected causes or co-carcinogens include other mineral fibres, simian virus 40 (SV40) and radiation. A mesothelioma epidemic in Turkey has demonstrated a probable genetic predisposition to mineral fibre carcinogenesis and studies of human tissues and animal models of mesothelioma have demonstrated genetic and epigenetic events that contribute to the multistep process of mineral fibre carcinogenesis. Several growth factors and their receptors have a significant role in the oncogenesis, progression and resistance to therapy of mesothelioma. Epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF) have been shown as targets for therapy based on promising preclinical data. However, clinical trials of tyrosine kinase inhibitors in mesothelioma have been disappointing. Bcl-XL is an important antiapoptotic member of the Bcl-2 family and is overexpressed in several solid tumours, including mesothelioma. Reduction of Bcl-XL expression in mesothelioma induces apoptosis and engenders sensitisation to cytotoxic chemotherapeutic agents. Pharmacological inhibitors of antiapoptotic Bcl-2 family members continue to undergo refinement and have shown promise in mesothelioma.

In plain English

This article was a 2012 narrative review, not a new study. It summarised published research on how malignant mesothelioma develops at the molecular level and on targeted drug treatments. Citing earlier work, the review stated that approximately 80% of mesothelioma cases can be directly attributed to asbestos exposure. It also stated that all asbestos fibre types possess carcinogenic potential, but that amphibole fibres are more likely than chrysotile to cause mesothelioma. Other suspected causes or co-carcinogens it named were erionite, simian virus 40 (SV40) and radiation. It described studies of a mesothelioma epidemic in Cappadocia, Turkey, which those studies attributed to an inherited predisposition to erionite-induced cancer. It also described reports of mutations in the BAP1 gene. It reviewed laboratory and animal studies, including the authors' own earlier work on blocking the protein Bcl-XL. It also reviewed clinical trials of targeted drugs, several of which were disappointing. The authors concluded that laboratory and animal studies of targeted therapies had been promising, but that randomised clinical trials of many of these same agents had been disappointing to date.

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 on the molecular pathogenesis and targeted therapy of malignant mesothelioma
• Who was studied: No study population of its own; the review drew on published studies of human cell lines and tissues, animal models, and clinical trials in mesothelioma patients
• Exposure: Asbestos (chrysotile and the amphiboles amosite, crocidolite and anthophyllite), discussed alongside other suspected causes or co-carcinogens: erionite, SV40 and radiation
• Main results:
  • Citing earlier work, the review stated that approximately 80% of mesothelioma cases can be directly attributed to asbestos fibre exposure
  • Citing a published review (Ref. 9), the article stated that all fibre types possess carcinogenic potential, but that amphibole exposure is more likely than chrysotile exposure to cause mesothelioma
  • Citing published studies (Ref. 2), the review stated that the Cappadocia epidemic was caused by a genetic predisposition to erionite-induced carcinogenesis, transmitted in an autosomal-dominant manner
  • Citing other studies, the review reported somatic BAP1 mutations in 23% of mesotheliomas and germline BAP1 mutations in two American families with a high incidence of mesothelioma
  • In a cited Phase II trial (CALGB 30101) of gefitinib in 43 chemotherapy-naive patients, the 3-month progression-free survival was 40%, which was not different from historical controls
  • In a cited Phase III placebo-controlled trial of Vorinostat in patients with advanced mesothelioma, overall survival was not significantly different between the Vorinostat and placebo groups
  • In earlier studies cited by the authors (Ref. 30), Bcl-XL antisense oligonucleotides combined with cisplatin reduced tumour growth and extended survival in mouse xenograft models of mesothelioma
• The authors' conclusion: The authors concluded that preclinical studies of targeted therapies (tyrosine kinase, HDAC and proteasome inhibitors) had been promising, but randomised clinical trials of many of these agents had been disappointing to date

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, Mesothelioma, Asbestos Exposure, SV40, Carcinogenesis, Oncogenesis, Clinical Trial.

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