Human mesothelioma cells and asbestos-exposed mesothelial cells are selectively resistant to amosite toxicity: a possible mechanism for tumor promotion by asbestos

Our plain-English summary of Human mesothelioma cells and asbestos-exposed mesothelial cells are selectively resistant to amosite toxicity: a possible mechanism for tumor promotion by asbestos, by E.W. Gabrielson, A. Van der Meeren, R.R. Reddel, et al (Carcinogenesis, 1992).

The study

• Authors: E.W. Gabrielson, A. Van der Meeren, R.R. Reddel, H. Reddel, B.I. Gerwin, C.C. Harris
• Journal: Carcinogenesis
• Published: 1992;13(8):1359-63
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

To determine if asbestos exposure could contribute to mesothelial cell carcinogenesis by selection and/or expansion of an initiated cell population, we compared normal human pleural mesothelial cells to either human mesothelioma cell lines or mesothelial cells transfected with cancer-related genes for sensitivity to amosite fibers in vitro. Neither normal nor mesothelioma cells were directly stimulated to replicate or increase DNA synthesis by any of the asbestos exposure conditions tested. The potential selective effect of asbestos exposure was demonstrated by a differential sensitivity of normal mesothelial cells and mesothelioma cells to amosite: for example, up to 20-fold higher concentrations of amosite fibers were required to inhibit replication of mesothelioma cell lines than normal mesothelial cells. In addition, a significant resistance (4-fold) to amosite toxicity was observed for SV40 immortalized mesothelial cell lines that had previously been selected in vitro for resistance to asbestos. SV40 immortalized cells that have become tumorigenic after transfection with either Ha-ras or PDGF A-chain genes were not significantly more resistant to the cytotoxic effects of amosite than primary normal cells, and the primary cells were equally sensitive to amosite as mesothelial cells that were only immortalized by SV40. The sensitivity of normal mesothelial cells to asbestos does not appear to be simply a result of general fragility of the mesothelial cells, since similar levels of hydrogen peroxide and silica were cytotoxic for normal mesothelial cells and mesothelioma cell lines. Because mesothelioma cells have a greater resistance to asbestos cytotoxicity than normal mesothelial cells, we hypothesize that a differential resistance to cell killing by asbestos fibers in vivo may result in a selective expansion of an initiated or transformed cell population and thus contribute to the carcinogenesis process. Since tumorigenicity and asbestos resistance occur independently of one another in genetically altered mesothelial cell lines, genotypic and phenotypic alterations that lead to tumorigenic conversion may not be the same changes that provide resistance to cell killing by asbestos.

In plain English

This laboratory cell-culture study compared how normal human pleural mesothelial cells and altered or malignant mesothelial cell lines responded to amosite asbestos fibers. Normal cells grown from pleural fluid of patients with non-malignant disease were compared with four human mesothelioma lines (VAMT-1, HuT 28, HuT 290, JMN), the SV40-immortalized line MeT-5A, MeT-5A derivatives made tumorigenic by Ha-ras or PDGF A-chain transfection, and two non-tumorigenic lines previously selected by surviving asbestos exposure (MeT-5A/AM and P19 A/T). Colony-forming efficiency and clonal growth rate were measured in these cells and DNA synthesis in normal cells and mesothelioma lines; amosite stimulated neither colony formation nor clonal growth in any cell type, and no asbestos-associated increase in DNA synthesis was seen. About 10- to 20-fold more amosite was required to inhibit the mesothelioma lines than the normal cells, and the two asbestos-selected lines were about 5-fold less sensitive than primary cells or MeT-5A, while the ras- and PDGF-transfected tumorigenic lines were not significantly more resistant than primary normal cells. Hydrogen peroxide and silica were toxic at similar concentrations for normal and mesothelioma cells.

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 experimental study of cultured human cells (cytotoxicity and DNA synthesis assays)
• Who was studied: Cultured normal human pleural mesothelial cells from patients with non-malignant disease; four human mesothelioma cell lines (VAMT-1, HuT290, HuT28, JMN); SV40-immortalized MeT-5A and its derivatives (MeT-5A/EJ-ras, MeT-A, MeT-5A/AM) and the asbestos-selected, SV40-immortalized P19 A/T line
• Exposure: Amosite asbestos fibers (UICC) added continuously to culture medium; alpha-quartz silica (Min-U-Sil) and hydrogen peroxide used as comparison agents
• Main results:
  • No growth stimulation by amosite in any cell type tested, by colony-forming efficiency or clonal growth rate
  • DNA synthesis was examined over 72 h in normal mesothelial cells and HuT 290 mesothelioma cells (and at 12, 24 and 36 h in HuT 28, VAMT and JMN), with no asbestos-associated increase
  • Mesothelioma cell lines needed roughly 10- to 20-fold more amosite for growth inhibition than normal mesothelial cells
  • The two asbestos-selected, SV40-immortalized lines (P19 A/T and MeT-5A/AM) were about 5-fold less sensitive to amosite than primary normal cells or MeT-5A
  • The tumorigenic lines transfected with Ha-ras or PDGF A-chain showed a difference of less than 2-fold and were, in the authors' terms, not significantly resistant to asbestos cytotoxicity
  • Differences in 50% inhibitory amosite levels between the normal cells and the asbestos-selected and mesothelioma lines reached statistical significance
  • Hydrogen peroxide and silica were cytotoxic at similar concentrations for normal mesothelial cells and mesothelioma lines (JMN, VAMT-1)
• The authors' conclusion: The authors proposed that the greater resistance of mesothelioma cells to amosite cytotoxicity could allow selective expansion of initiated or transformed cells, and noted that resistance tracked with prior asbestos exposure rather than with tumorigenic conversion
• Limitations the authors state:
  • The authors stated that the cellular mechanism of the mesothelioma cells' resistance to asbestos was unknown
  • The authors noted that asbestos and silica exposure had to be continuous because the particles could not be removed from the culture plates
  • The authors noted that proliferative signals might occur at doses already cytotoxic to the highly sensitive mesothelial cell and so could not be detected

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Mesothelial Cells, Amosite, Asbestos Exposure, Carcinogenesis, SV40, Platelet-Derived Growth Factor (PDGF).

Related studies

• Ascorbic acid modifies the surface of asbestos: possible implications in the molecular mechanisms of toxicity — G. Martra, M. Tomatis, et al. (2003)
• Cytotoxicity of oxidants and asbestos fibers in cultured human mesothelial cells — V.L. Kinnula, K. Aalto, et al. (1994)
• Soluble ICAM-1, MCP-1, and MIP-2 protein secretion by rat pleural mesothelial cells following exposure to amosite asbestos — G.D. Hill, J.B. Mangum, et al. (2003)
• Ferritin adsorption on amosite fibers: possible implications in the formation and toxicity of asbestos bodies — B. Fubini, F. Barceló, et al. (1997)
• A possible mechanism of chrysotile asbestos toxicity — G.L. Fisher, B.T. Mossman, et al. (1987)
• Studies on the role of oxygen radicals in asbestos-induced cytopathology of cultured human lung mesothelial cells — E.W. Gabrielson, G.M. Rosen, et al. (1986)

Browse more research in Carcinogenesis, or return to medical research.