How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations

Our plain-English summary of How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations, by H. Rehrauer, L. Wu, W. Blum, et al (Oncogene, 2018).

The study

• Authors: H. Rehrauer, L. Wu, W. Blum, L. Pecze, T. Henzi, V. Serre-Beinier, C. Aquino, B. Vrugt, M. de Perrot, B. Schwaller, E. Felley-Bosco
• Journal: Oncogene
• Published: 2018;37(20):2645-2659
• Cited by: 52 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Chronic exposure to intraperitoneal asbestos triggered a marked response in the mesothelium well before tumor development. Macrophages, mesothelial precursor cells, cytokines, and growth factors accumulated in the peritoneal lavage. Transcriptome profiling revealed YAP/TAZ activation in inflamed mesothelium with further activation in tumors, paralleled by increased levels of cells with nuclear YAP/TAZ. Arg1 was one of the highest upregulated genes in inflamed tissue and tumor. Inflamed tissue showed increased levels of single-nucleotide variations, with an RNA-editing signature, which were even higher in the tumor samples. Subcutaneous injection of asbestos-treated, but tumor-free mice with syngeneic mesothelioma tumor cells resulted in a significantly higher incidence of tumor growth when compared to naïve mice supporting the role of the environment in tumor progression.

In plain English

This was an animal experiment in Nf2 heterozygous C57Bl/6J mice given eight intraperitoneal injections of UICC-grade crocidolite asbestos (400 micrograms per mouse) every three weeks, with saline-injected sham mice. In crocidolite-exposed mice that had not developed mesothelioma, CD68/F480 macrophages in the peritoneal lavage were five-fold higher than in sham mice, while T and B cell numbers in the lavage were significantly decreased and cytokines, chemokines and growth factors were more abundant. RNA sequencing of scraped mesothelium found 5976 differentially expressed genes between crocidolite-exposed and sham tissue, with Arg1 among the most strongly upregulated, and more single-nucleotide variations, including a significant rise in A to G changes consistent with RNA editing; tissue staining showed a progressive rise in nuclear YAP in benign growths and tumors. When tumor-free asbestos-exposed mice were injected subcutaneously with syngeneic RN5 mesothelioma cells, one developed a peritoneal mesothelioma and all others developed subcutaneous tumors within 50 days, whereas two naive mice remained tumor-free at 150 days. The authors concluded that YAP/TAZ activation, RNA editing and an altered environment precede tumor development.

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 (mouse asbestos exposure model) with flow cytometry, cytokine measurement, RNA-seq transcriptome and variant profiling, immunohistochemistry, plus supporting cell-line experiments and a tumor-cell challenge experiment
• Who was studied: C57Bl/6J Nf2 heterozygous mice: 50 crocidolite-exposed (33 male, 17 female) and 37 sham-injected (19 male, 18 female), aged 6-8 weeks at first injection; also human mesothelioma cell lines SPC111 and NCI-H226
• Exposure: UICC-grade crocidolite asbestos, 400 micrograms per mouse, injected intraperitoneally every 3 weeks for eight rounds; sham mice received saline
• Main results:
  • In mesothelioma-free crocidolite-exposed mice, peritoneal lavage macrophages were five-fold higher than in sham-exposed mice
  • T and B cell numbers in the peritoneal lavage of crocidolite-treated mice were significantly decreased
  • Cytokines, chemokines and growth factors measured in peritoneal lavage were all higher in crocidolite-exposed mice
  • 5976 genes were differentially expressed between crocidolite-exposed and sham mesothelium
  • 8416 genes were differentially expressed between crocidolite-exposed mice with tumors and crocidolite-exposed mice without tumors
  • The increase in A to G changes in crocidolite-exposed tissue was significant for absolute counts (p = 0.005) and for the relative fraction of total mutations (p = 0.00031)
  • A to G alterations rose while the complementary T to C alterations did not, which the authors took as a mark of RNA editing
  • Adar expression was 3.9-fold higher in inflamed tissue than in sham tissue
  • Arg1 was among the most upregulated genes in crocidolite-exposed tissue versus sham, with further upregulation in tumors
  • By immunohistochemistry, nuclear YAP localization and Ki-67 increased progressively in benign growth and tumor tissue of crocidolite-exposed mice
  • After subcutaneous RN5 mesothelioma cell injection, one asbestos-exposed mouse developed a peritoneal mesothelioma and all the other asbestos-exposed mice grew a subcutaneous tumor within 50 days, while two naive mice were tumor-free at 150 days
• The authors' conclusion: The authors concluded that their analysis suggests progressive activation of YAP/TAZ-dependent transcription, accumulation of RNA-editing-type single nucleotide variations, and a possible role for immunosuppressive macrophages and/or mesothelial precursor cells in tumor development after asbestos exposure
• Limitations the authors state:
  • The authors could not assess microRNA abundance or mutations because of the RNA extraction method used
  • The authors stated that the cell types proliferating after asbestos exposure are not known
  • The authors noted that disease penetrance in this model was low, 10% in this study using Nf2 heterozygote mice
  • One crocidolite non-tumor sample with a very high mutation count and intermediate expression profile was excluded from the expression analysis
  • Sample sizes were not set by formal statistical calculation

Topics

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

Medical terms in this study, explained in our Lexicon: Macrophage, Somatic Mutation, Mesothelium, Cytokine, Mesothelioma.

Related studies

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• Immunohistochemistry for NF2, LATS1/2, and YAP/TAZ Fails to Separate Benign From Malignant Mesothelial Proliferations — B.S. Sheffield, J. Lorette, et al. (2016)
• TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation — A. Matsushita, T. Sato, et al. (2019)
• YAP/TAZ activation predicts clinical outcomes in mesothelioma and is conserved in in vitro model of driver mutations — R. Cunningham, S. Jia, et al. (2023)
• Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing — A. Miyanaga, M. Masuda, et al. (2015)
• Pathogenesis of mesothelial reactions to asbestos fibers. Monocyte recruitment and macrophage activation — R.M. Branchaud, L.J. Garant, et al. (1993)

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