Epithelial to Mesenchymal Transition in Human Mesothelial Cells Exposed to Asbestos Fibers: Role of TGF-β as Mediator of Malignant Mesothelioma Development or Metastasis via EMT Event

Our plain-English summary of Epithelial to Mesenchymal Transition in Human Mesothelial Cells Exposed to Asbestos Fibers: Role of TGF-β as Mediator of Malignant Mesothelioma Development or Metastasis via EMT Event, by S. Turini, L. Bergandi, E. Gazzano, et al (International Journal of Molecular Sciences, 2019).

The study

• Authors: S. Turini, L. Bergandi, E. Gazzano, M. Prato, E. Aldieri
• Journal: International Journal of Molecular Sciences
• Published: 2019;20(1)
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos exposure increases the risk of asbestosis and malignant mesothelioma (MM). Both fibrosis and cancer have been correlated with the Epithelial to Mesenchymal Transition (EMT)-an event involved in fibrotic development and cancer progression. During EMT, epithelial cells acquire a mesenchymal phenotype by modulating some proteins. Different factors can induce EMT, but Transforming Growth Factor β (TGF-β) plays a crucial role in promoting EMT. In this work, we verified if EMT could be associated with MM development. We explored EMT in human mesothelial cells (MeT-5A) exposed to chrysotile asbestos: we demonstrated that asbestos induces EMT in MeT-5A cells by downregulating epithelial markers E-cadherin, β-catenin, and occludin, and contemporarily, by upregulating mesenchymal markers fibronectin, α-SMA, and vimentin, thus promoting EMT. In these cells, this mechanism is mediated by increased TGF-β secretion, which in turn downregulates E-cadherin and increases fibronectin. These events are reverted in the presence of TGF-β antibody, via a Small Mother Against Decapentaplegic (SMAD)-dependent pathway and its downstream effectors, such as Zinc finger protein SNAI1 (SNAIL-1), Twist-related protein (Twist), and Zinc Finger E-Box Binding Homeobox 1 (ZEB-1), which downregulate the E-cadherin gene. Since SNAIL-1, Twist, and ZEB-1 have been shown to be overexpressed in MM, these genes could be considered possible predictive or diagnostic markers of MM development.

In plain English

This was a laboratory study at the University of Torino, Italy, on a line of human mesothelial cells called MeT-5A. Cells were exposed for 72 hours to UICC chrysotile asbestos at 5 µg/cm2, or to the growth factor TGF-β, and were compared with untreated cells. The authors looked for epithelial to mesenchymal transition (EMT), a change in cell type they describe as involved in fibrosis and cancer progression. Chrysotile-exposed cells became more elongated and thinner. They had lower levels of E-cadherin, β-catenin and occludin and higher levels of fibronectin, vimentin and α-SMA, and released more MMP-2 and TGF-β. Adding an antibody that blocks TGF-β restored E-cadherin and fibronectin levels, though the authors said this recovery was not total. Exposed cells also showed more phosphorylation of SMAD-2 (which the authors call activation) and of GSK-3β (which they call inactivation), SNAIL-1 build-up in the nucleus, and, the authors reported, more Twist and ZEB-1. The authors concluded that chrysotile induced EMT in these cells through TGF-β. They hypothesized that this mechanism is involved in mesothelioma development or metastasis. They called TGF-β just one possible mediator.

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: Laboratory (in vitro) cell culture experiment
• Who was studied: A commercially obtained human mesothelial cell line (MeT-5A, from the American Type Culture Collection), studied at the Department of Oncology, University of Torino, Italy; experiments were repeated three times
• Exposure: UICC chrysotile asbestos, sonicated to separate fiber bundles, at 5 µg/cm2 for 72 hours; recombinant TGF-β was used as a comparison treatment, and a neutralizing anti-TGF-β antibody was used in blocking experiments
• Main results:
  • Cells exposed to chrysotile or TGF-β took on a spindle-shaped, fibroblast-like shape and looked more elongated and thinner than untreated cells
  • In chrysotile- or TGF-β-exposed cells, the epithelial marker E-cadherin was significantly decreased, and β-catenin and occludin were also reduced, compared with untreated cells (Western blot significance p less than 0.001)
  • In chrysotile- or TGF-β-exposed cells, the mesenchymal markers fibronectin, vimentin and α-SMA were significantly increased compared with untreated cells
  • At the gene (mRNA) level, E-cadherin decreased and fibronectin increased after chrysotile or TGF-β exposure
  • Chrysotile- or TGF-β-exposed cells released more MMP-2 than untreated cells
  • Chrysotile-exposed cells secreted significantly more TGF-β (p less than 0.001), and a TGF-β-blocking antibody restored E-cadherin and fibronectin levels
  • Chrysotile, like TGF-β, increased SMAD-2 phosphorylation, which the authors describe as its activation
  • Chrysotile exposure increased phosphorylation of GSK-3β, which the authors describe as inactivating it, together with accumulation of SNAIL-1 in the cell nucleus
  • The authors reported overexpression of SNAIL-1, Twist and ZEB-1 after chrysotile exposure, with downregulation of E-cadherin
• The authors' conclusion: The authors concluded that chrysotile induces EMT in MeT-5A cells through a mechanism involving TGF-β, GSK-3β and SNAIL-1. They hypothesized that this mechanism is involved in malignant mesothelioma development and/or metastasis. They suggested that SNAIL-1, Twist and ZEB-1 might be explored as predictive markers or treatment targets.
• Limitations the authors state:
  • Blocking TGF-β did not fully restore the markers, which the authors explain by TGF-β being only one of the possible mediators
  • The proposed mechanism is only one of several possible mechanisms
  • The authors state that a clear mechanism linking asbestos to EMT has not yet been elucidated

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelial Cells, Malignant Mesothelioma, Metastasis, Asbestos Exposure, Fibrosis, Chrysotile, MeT-5A Cells.

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• Clinical significance of epithelial-mesenchymal transition-associated markers in malignant pleural mesothelioma — T. Iwanami, H. Uramoto, et al. (2014)
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• APE-1/Ref-1 Inhibition Blocks Malignant Pleural Mesothelioma Cell Proliferation and Migration: Crosstalk between Oxidative Stress and Epithelial Mesenchymal Transition (EMT) in Driving Carcinogenesis and Metastasis — V. Ramundo, G. Zanirato, et al. (2023)
• FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal — K. Schelch, C. Wagner, et al. (2018)

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