Increased expression of epidermal growth factor receptor in rat pleural mesothelial cells correlates with carcinogenicity of mineral fibres

Our plain-English summary of Increased expression of epidermal growth factor receptor in rat pleural mesothelial cells correlates with carcinogenicity of mineral fibres, by S.P. Faux, C.E. Houghton, A. Hubbard, et al (Carcinogenesis, 2000).

The study

• Authors: S.P. Faux, C.E. Houghton, A. Hubbard, G. Patrick
• Journal: Carcinogenesis
• Published: 2000;21(12):2275-80
• Cited by: 37 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Asbestos fibres have been shown to stimulate the mitogen-activated protein kinase signalling cascade in rat pleural mesothelial (RPM) cells after autophosphorylation of the epidermal growth factor receptor (EGFR). We examined if mineral fibres with known carcinogenicity can be discriminated from materials with less or no carcinogenicity by their ability to up-regulate expression of EGFR protein in RPM cells in vitro. Crocidolite and erionite, two fibrous preparations with marked potential to induce mesothelioma, were associated with increases in EGFR protein expression over sham controls, whereas chrysotile asbestos and milled (non-fibrous) crocidolite did not. Intense patterns of EGFR protein expression were linked to RPM cells phagocytosing long fibres. To determine the role of EGFR expression in these cells, we assessed cell proliferation using an antibody against proliferating cell nuclear antigen (PCNA) in combination with an antibody against EGFR. In these co-localization studies, cells showed intense staining for EGFR protein 24 h before being PCNA positive at 48 h. These results suggest that carcinogenic fibres induce EGFR and initiate cell signalling cascades in mesothelial cells, leading to cell proliferation and carcinogenesis.

In plain English

This laboratory study grew pleural lining (mesothelial) cells from male Fischer 344 rats. It tested whether fibres known to cause mesothelioma could be told apart from less carcinogenic materials by whether they raised levels of a growth-signal receptor, EGFR, in these cells. The cells were exposed to crocidolite asbestos, erionite, chrysotile asbestos or milled (non-fibrous) crocidolite. Crocidolite and erionite increased EGFR compared with sham controls, while chrysotile and milled crocidolite did not. Averaged over 10 random microscope fields, intense staining was seen in 45.46% (standard deviation 4.54) of crocidolite-treated cells and 40% (standard deviation 7.62) of erionite-treated cells, against 0% for control, milled crocidolite and chrysotile. Cells trying to engulf long crocidolite fibres stained most strongly. With crocidolite, the EGFR increase appeared from 8 hours and lasted to 72 hours. A marker of cell proliferation (PCNA) appeared at 48 and 72 hours, after the EGFR increase. Two blocking drugs, one a selective EGFR inhibitor, significantly reduced a downstream signal (AP-1 binding). The authors concluded that the fibres with the greatest potential to cause mesothelioma showed the most marked EGFR increase. The work used rat cells, not people.

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: In vitro laboratory experiment on cultured rat cells
• Who was studied: Rat pleural mesothelial (RPM) cells taken from male Fischer 344 rats aged 12 to 20 weeks, studied at the MRC Toxicology Unit, University of Leicester, UK
• Exposure: NIEHS crocidolite (mean length 11.4 µm, mean diameter 0.27 µm), UICC chrysotile (1.1 µm long, 0.04 µm diameter), milled crocidolite (no fibres seen) and erionite from Rome, Oregon (6.0 µm long, 0.8 µm diameter), each at 5.0 µg/cm2, for 2, 8, 24, 48 or 72 h. TNFα was used as a positive control.
• Main results:
  • Crocidolite and erionite increased EGFR protein expression over sham controls, producing intense patterns of expression. Milled crocidolite and chrysotile did not increase EGFR staining over the sham control.
  • In Table II, results are means with standard deviations across 10 random microscope fields. Intense EGFR staining was seen in a mean of 45.46% (SD 4.54) of crocidolite-treated cells and 40% (SD 7.62) of erionite-treated cells. It was seen in 0% of control, milled crocidolite and chrysotile cells.
  • Cells attempting to engulf long crocidolite fibres showed increased EGFR staining. Cells in contact with a number of shorter fibres showed negligible staining.
  • Cycloheximide, a blocker of protein synthesis, abolished the crocidolite-induced EGFR increase. The increase was seen only after 8 h of fibre exposure and continued for 72 h.
  • At 24 h, the active (phosphorylated) form of EGFR was greater in crocidolite-treated cells than in sham controls.
  • In crocidolite-treated cells, EGFR increased at 24 h, and both EGFR and PCNA, a marker of cell proliferation, increased at 48 and 72 h. PCNA did not increase at 8 h or 24 h.
  • Suramin, and separately the EGFR inhibitor tyrphostin AG 1478, significantly reduced crocidolite-induced increases in AP-1 DNA binding activity.
• The authors' conclusion: The authors concluded that the fibres with the greatest potential to induce mesothelioma showed the most marked up-regulation and activation of EGFR in rat pleural mesothelial cells. They wrote that this supports the view that chronic EGFR expression and subsequent cell proliferation are involved in the chain of events leading from asbestos exposure to cancer.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelial Cells, EGFR, Crocidolite, erionite, Mesothelioma, Chrysotile, Carcinogenic, Carcinogenesis.

Related studies

• Increased epidermal growth factor-receptor protein in a human mesothelial cell line in response to long asbestos fibers — J.C. Pache, Y.M. Janssen, et al. (1998)
• Asbestos-induced phosphorylation of epidermal growth factor receptor is linked to c-fos and apoptosis — C.L. Zanella, C.R. Timblin, et al. (1999)
• Patterns of c-fos and c-jun proto-oncogene expression, apoptosis, and proliferation in rat pleural mesothelial cells exposed to erionite or asbestos fibers — C.R. Timblin, G.D. Guthrie, et al. (1998)
• Role of iron in inactivation of epidermal growth factor receptor after asbestos treatment of human lung and pleural target cells — A. Baldys, A.E. Aust (2005)
• Expression of growth factor and growth factor receptor RNA in rat pleural mesothelial cells in culture — E. Bermudez, J. Everitt, et al. (1990)
• Asbestos upregulates expression of the urokinase-type plasminogen activator receptor on mesothelial cells — R.C. Perkins, V.C. Broaddus, et al. (1999)

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