Asbestos accelerates disease onset in a genetic model of malignant pleural mesothelioma

Our plain-English summary of Asbestos accelerates disease onset in a genetic model of malignant pleural mesothelioma, by P. Farahmand, K. Gyuraszova, C. Rooney, et al (Frontiers in Toxicology, 2023).

The study

• Authors: P. Farahmand, K. Gyuraszova, C. Rooney, X.L. Raffo-Iraolagoitia, G. Jayasekera, A. Hedley, E. Johnson, T. Chernova, G. Malviya, H. Hall, T. Monteverde, K. Blyth, R. Duffin, L.M. Carlin, D. Lewis, J. Le Quesne, M. MacFarlane, D.J. Murphy
• Journal: Frontiers in Toxicology
• Published: 2023;5:1200650
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Hypothesis: Asbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations. Methods: Genetically modified conditional allelic mice that were previously shown to develop mesothelioma in the absence of exposure to asbestos were induced with lentiviral vector expressing Cre recombinase with and without intrapleural injection of amosite asbestos and monitored until symptoms required euthanasia. Resulting tumours were examined histologically and by immunohistochemistry for expression of lineage markers and immune cell infiltration. Results: Injection of asbestos dramatically accelerated disease onset and end-stage tumour burden. Tumours developed in the presence of asbestos showed increased macrophage infiltration. Pharmacological suppression of macrophages in mice with established tumours failed to extend survival or to enhance response to chemotherapy. Conclusion: Asbestos-driven inflammation contributes to the severity of mesothelioma beyond the acquisition of rate-limiting mutations, however, targeted suppression of macrophages in established epithelioid mesothelioma showed no therapeutic benefit.

Copyright © 2023 Farahmand, Gyuraszova, Rooney, Raffo-Iraolagoitia, Jayasekera, Hedley, Johnson, Chernova, Malviya, Hall, Monteverde, Blyth, Duffin, Carlin, Lewis, Le Quesne, MacFarlane and Murphy.

In plain English

This was an animal experiment in genetically modified mice. Mice carrying Cdkn2a nullizygous and floxed Nf2 and Trp53 alleles (abbreviated CNP), which develop mesothelioma without fibre exposure, were given a single intrapleural injection of 10^7 pfu lentiviral vector expressing Cre recombinase, with or without a single intrapleural injection of 25 µg long fibre amosite asbestos 10 days later, and were monitored until symptoms required euthanasia. Mice given asbestos (N = 17) required euthanasia at a median of 88 days post induction, compared with 148 days for those not given asbestos (N = 9; p < 0.001, Mantel Cox logrank). Tumour burden was visibly greater with asbestos; tumours arising in CNP mice were predominantly (greater than 90%) epithelioid, a histology the authors reported irrespective of asbestos exposure. F4/80-positive macrophage infiltration was increased in tumours from asbestos-treated mice, while most other tumour-infiltrating immune populations showed no quantitative difference. The CSF1R inhibitor AZD7507 suppressed macrophages but gave no survival benefit on its own, and added no benefit over cisplatin plus pemetrexed chemotherapy alone. The authors concluded asbestos-driven inflammation adds to mesothelioma severity beyond rate-limiting mutations.

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: animal experiment in genetically engineered mice, with survival, histology, immunohistochemistry, flow cytometry, imaging, RNA sequencing and drug treatment arms
• Who was studied: Adult (8-10 week old) Cdkn2a-/-;Nf2fl/fl;Trp53fl/fl ("CNP") mice, both sexes in approximately equal numbers; 17 induced with lenti-Cre plus asbestos and 9 with lenti-Cre alone, plus 3 uninduced mice given asbestos only; study carried out in Glasgow and Cambridge, United Kingdom
• Exposure: Single intrapleural injection of 25 µg long fibre amosite asbestos per mouse, given 10 days after intrapleural injection of 10^7 viral particles of lentiviral Cre recombinase
• Main results:
  • Mice induced with lenti-Cre plus asbestos required euthanasia at a median of 88 days post induction, versus a median of 148 days for mice induced without asbestos (p < 0.001)
  • Asbestos given to uninduced CNP mice produced no symptomatic disease in the same timeframe; such mice examined 10 months later showed reactive pleural thickening but no tumour
  • Tumours arising in CNP mice overall were predominantly (greater than 90%) epithelioid, with a small subset showing discrete sarcomatoid regions; tumour burden was visibly greater in asbestos-treated mice
  • In the asbestos-treated group, F4/80-positive macrophages in tumours were increased (6 mice from each cohort; p < 0.0001, T-test), while most other tumour-infiltrating immune populations did not differ
  • Immunohistochemistry of size-matched tumours showed no consistent difference in WT1 or Ki67 expression between mice with and without asbestos
  • The CSF1R inhibitor AZD7507 given from day 60 suppressed tumour macrophage infiltration (treated N = 5, vehicle N = 6) but gave no survival benefit (AZD7507 N = 7 versus vehicle N = 8, not significant)
  • Adding AZD7507 to two rounds of cisplatin plus pemetrexed (N = 12 with, N = 10 without) gave no additional benefit over chemotherapy alone
  • In pleural lavage of asbestos-exposed induced mice, leukocyte infiltration increased over time, with a significant rise in B, CD8+, CD4+ and gamma-delta T cells and small cavity macrophages between day 60 and day 75 post induction
  • No off-target tumours in other tissues were detected in this model, with or without asbestos
• The authors' conclusion: The authors concluded that asbestos-driven inflammation adds to the severity of mesothelioma beyond the acquisition of rate-limiting mutations, but that targeted suppression of macrophages in established epithelioid mesothelioma gave no therapeutic benefit
• Limitations the authors state:
  • The authors stated they could not rule out that the acceleration came from additional asbestos-driven mutations
  • The authors stated it was unclear whether the absence of off-target tumours was due to the lentiviral vector, the lower virus dose, or both
  • The authors stated it remained to be determined whether macrophage suppression could enhance other treatments or work against sarcomatoid disease
  • For F4/80 staining the authors reported accurate cell counts could not be obtained, so data were given as stained tumour area
  • Some supporting observations were reported only as unpublished data not shown

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Inflammation, Mesothelioma, Amosite, Immunohistochemistry, Macrophage, Chemotherapy, Epithelioid.

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• Development and characterization of a rapid-onset rodent inhalation model of asbestosis for disease prevention — B.T. Mossman, Y.M. Janssen, et al. (1991)
• Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations — Y. Kadariya, M. Cheung, et al. (2016)
• Is there a "genetic model" in the genesis of malignant pleural mesothelioma? — J.A. Precerutti, M. Mayorga, et al. (1990)
• Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma — J. Xu, Y. Kadariya, et al. (2014)
• Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis — D.A. Altomare, C.W. Menges, et al. (2011)
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