Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

Our plain-English summary of Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo, by D.W. Greening, H. Ji, M. Chen, et al (Scientific Reports, 2016).

The study

• Authors: D.W. Greening, H. Ji, M. Chen, B.W. Robinson, I.M. Dick, J. Creaney, R.J. Simpson
• Journal: Scientific Reports
• Published: 2016;6:32643
• Cited by: 84 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets.

In plain English

This laboratory study examined exosomes, tiny packages that cells release, from four human mesothelioma cell lines (JO38, JU77, OLD1612, LO68). The lines came from different patients with malignant pleural mesothelioma at the National Centre for Asbestos Related Diseases in Australia. The study did not measure asbestos exposure. Using mass spectrometry, the authors identified 2,178 proteins in the exosomes. Of these, 631 were found in all four cell lines' exosomes, and 506 were not previously listed in the Vesiclepedia vesicle database. Using that database and earlier studies, the authors defined a 570-protein mesothelioma exosome signature. The exosomes carried 111 proteins linked to immune regulation and 16 tumour antigens, including mesothelin. In lab dishes, exosomes from some cell lines significantly increased migration of mouse and human fibroblasts and human blood-vessel lining cells. They also increased tube formation by the blood-vessel cells. The authors concluded that these exosomes are potential targets for circulating markers of mesothelioma. They noted that whether the immune-related proteins are functionally active, in the exosomes or in the cells receiving them, remains to be determined.

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) study: proteomic profiling of exosomes from human mesothelioma cell lines, plus cell migration and tube formation assays
• Who was studied: Four human mesothelioma cell lines (JO38, JU77, OLD1612, LO68) established from different patients with malignant pleural mesothelioma at the National Centre for Asbestos Related Diseases (NCARD), Australia
• Exposure: No asbestos or fiber exposure was studied. In the functional experiments, fibroblasts and endothelial cells were exposed to exosomes from the mesothelioma cells.
• Main results:
  • A total of 2,178 proteins were identified in exosomes from the four mesothelioma cell lines
  • 631 proteins were common to exosomes from all four cell lines
  • 506 of 2,178 proteins (23%) had not previously been reported in the Vesiclepedia database
  • The authors defined a mesothelioma exosome protein signature (mEXOS) of 570 proteins
  • 111 proteins associated with immunoregulation were identified in the mesothelioma-derived exosomes
  • 16 tumour-derived antigens, including mesothelin, were identified as exosome cargo
  • Compared with vehicle-treated cells, exosomes from JO38, OLD1612 and LO68 significantly increased mouse embryonic fibroblast (MEF) migration
  • Exosomes from JU77 and OLD1612 significantly increased neoHFF fibroblast migration
  • Exosomes from JO38, OLD1612 and LO68 significantly increased migration of HUVEC endothelial cells
  • Mesothelioma-derived exosomes increased HUVEC tube length formation compared with vehicle-treated cells
• The authors' conclusion: The authors concluded that tumour-derived exosomes and their cargo are potential targets for circulating markers of mesothelioma and for designing targeted immunomodulatory therapies
• Limitations the authors state:
  • Whether the immune-related exosome components are functionally active, in the exosomes or in recipient cells, remains to be determined
  • The findings come from mesothelioma cell models grown in the laboratory (in vitro), and correlation with patient biofluids is still needed

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Mesothelioma, Metastasis, Angiogenesis, Fibroblast.

Related studies

• Mouse serum exosomal proteomic signature in response to asbestos exposure — P. Munson, Y.W. Lam, et al. (2018)
• A Proteomic Analysis of the Malignant Mesothelioma Secretome Using iTRAQ — J. Creaney, I.M. Dick, et al. (2017)
• Exosomes from asbestos-exposed cells modulate gene expression in mesothelial cells — P. Munson, Y.W. Lam, et al. (2018)
• Potential Roles of Exosomes in the Development and Detection of Malignant Mesothelioma: An Update — P. Munson, A. Shukla (2022)
• Exosomal miR-16-5p as a target for malignant mesothelioma — P.B. Munson, E.M. Hall, et al. (2019)
• Comparative proteomic analysis of malignant pleural mesothelioma evidences an altered expression of nuclear lamin and filament-related proteins — L. Giusti, Y. Da Valle, et al. (2014)

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