Extracellular Vesicles Isolated from Malignant Mesothelioma Cancer-Associated Fibroblasts Induce Pro-Oncogenic Changes in Healthy Mesothelial Cells

Our plain-English summary of Extracellular Vesicles Isolated from Malignant Mesothelioma Cancer-Associated Fibroblasts Induce Pro-Oncogenic Changes in Healthy Mesothelial Cells, by T. Chernova, S. Grosso, X.M. Sun, et al (International Journal of Molecular Sciences, 2022).

The study

• Authors: T. Chernova, S. Grosso, X.M. Sun, A.R. Tenor, J.Z. Cabeza, A. Craxton, E.L. Self, A. Nakas, K. Cain, M. MacFarlane, A.E. Willis
• Journal: International Journal of Molecular Sciences
• Published: 2022;23(20)
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is an aggressive tumour of the pleura (MPM) or peritoneum with a clinical presentation at an advanced stage of the disease. Current therapies only marginally improve survival and there is an urgent need to identify new treatments. Carcinoma-associated fibroblasts (CAFs) represent the main component of a vast stroma within MPM and play an important role in the tumour microenvironment. The influence of CAFs on cancer progression, aggressiveness and metastasis is well understood; however, the role of CAF-derived extracellular vesicles (CAF-EVs) in the promotion of tumour development and invasiveness is underexplored. We purified CAF-EVs from MPM-associated cells and healthy dermal human fibroblasts and examined their effect on cell proliferation and motility. The data show that exposure of healthy mesothelial cells to EVs derived from CAFs, but not from normal dermal human fibroblasts (NDHF) resulted in activating pro-oncogenic signalling pathways and increased proliferation and motility. Consistent with its role in suppressing Yes-Associated Protein (YAP) activation (which in MPM is a result of Hippo pathway inactivation), treatment with Simvastatin ameliorated the pro-oncogenic effects instigated by CAF-EVs by mechanisms involving both a reduction in EV number and changes in EV cargo. Collectively, these data determine the significance of CAF-derived EVs in mesothelioma development and progression and suggest new targets in cancer therapy.

In plain English

This laboratory study looked at tiny packages called extracellular vesicles (EVs) released by fibroblasts, a type of supporting cell. Some came from cancer-associated fibroblasts (CAFs) from mesothelioma tumours of 8 surgical patients (cultures from at least 3 were used); others came from normal skin fibroblasts. The study did not test asbestos exposure. The authors added each kind of EV to normal human mesothelial cells (the LP-9 line) in dishes. After 20 hours, more than 90% of the mesothelial cells had taken up CAF EVs. EVs from CAFs, but not from normal fibroblasts, switched on cancer-associated signalling pathways, raised the cells' protein production, and made the cells move faster and farther. CAFs treated with the statin drug simvastatin released fewer EVs (48.7%, plus or minus 13.4%, of untreated levels; 3 patients). The EV contents also changed, and signalling in the mesothelial cells was switched on less strongly. The authors concluded that CAF-derived EVs matter in mesothelioma development and progression and suggest new treatment targets. They noted that limited EV amounts meant standard EV guidelines were not fully followed.

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 experiments using primary cells from patient tumours and a normal mesothelial cell line
• Who was studied: Cancer-associated fibroblasts isolated from resected mesothelioma tumours of 8 patients, with cultures from at least 3 patients used in downstream assays; normal dermal human fibroblasts; and normal untransformed human mesothelial cells (LP-9). The work was done in the UK (Cambridge and Leicester). Study dates are not given.
• Exposure: Normal mesothelial cells were treated with EVs from cancer-associated fibroblasts or from normal dermal fibroblasts. In some experiments the fibroblasts were first treated with 500 nM simvastatin for 24 h. No asbestos exposure was tested.
• Main results:
  • Fibroblast Activation Protein was detected in cancer-associated fibroblasts but not in normal dermal fibroblasts
  • After 20 h, more than 90% of LP-9 mesothelial cells had taken up labelled CAF-derived EVs
  • CAF-derived EVs increased activation of pro-oncogenic signalling pathways in LP-9 cells; EVs from normal dermal fibroblasts did not
  • Protein synthesis in LP-9 cells was significantly increased by CAF-EV treatment
  • CAF-derived EVs, but not normal-fibroblast-derived EVs, increased the speed and distance moved by LP-9 cells
  • Simvastatin-treated CAFs released 48.7 plus or minus 13.4% (mean plus or minus SD, 3 patients) of the EVs released by matched untreated CAFs
  • EVs from simvastatin-treated CAFs produced less signalling activation in LP-9 cells than EVs from untreated CAFs
  • Over 600 proteins were found in CAF-EV contents, and simvastatin altered the presence of over 400 of them
• The authors' conclusion: The authors concluded that CAF-derived EVs transfer material that gives normal mesothelial cells pro-oncogenic features. They also concluded that simvastatin lessened these effects by reducing EV numbers and changing EV contents, and that this suggests new targets for cancer therapy.
• Limitations the authors state:
  • Because EVs could only be isolated in limited amounts, the MISEV guidelines for EV studies were not fully followed

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Fibroblast, Mesothelial Cells, Pleura, Peritoneum, Carcinoma, Metastasis, Mesothelioma.

Related studies

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• Small Extracellular Vesicle-Derived Circular RNA hsa_circ_0007386 as a Biomarker for the Diagnosis of Pleural Mesothelioma — S. Zhand, J. Liao, et al. (2024)
• Extracellular vesicles as biomarkers in malignant pleural mesothelioma: A review — T. Ahmadzada, S. Kao, et al. (2020)
• Diagnostic and Prognostic Utility of the Extracellular Vesicles Subpopulations Present in Pleural Effusion — J. Javadi, A. Görgens, et al. (2021)
• Loss of NF2 Induces TGFβ Receptor 1-mediated Noncanonical and Oncogenic TGFβ Signaling: Implication of the Therapeutic Effect of TGFβ Receptor 1 Inhibitor on NF2 Syndrome — J.H. Cho, A.Y. Oh, et al. (2018)
• Small and Large Extracellular Vesicles Derived from Pleural Mesothelioma Cell Lines Offer Biomarker Potential — T. Ahmadzada, A. Vijayan, et al. (2023)

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