Exosomal transfer of miR-126 promotes the anti-tumour response in malignant mesothelioma: Role of miR-126 in cancer-stroma communication

MiR-126 has been shown to suppress malignant mesothelioma (MM) by targeting cancer-related genes without inducing toxicity or histopathological changes. Exosomes provide the opportunity to deliver therapeutic cargo to cancer stroma. Here, a tumour stromal model composed of endothelial cells (HUVECs)...

Full description

Saved in:
Bibliographic Details
Published in:Cancer letters 2019-10, Vol.463, p.27-36
Main Authors: Monaco, Federica, Gaetani, Simona, Alessandrini, Federica, Tagliabracci, Adriano, Bracci, Massimo, Valentino, Matteo, Neuzil, Jiri, Amati, Monica, Bovenzi, Massimo, Tomasetti, Marco, Santarelli, Lory
Format: Article
Language:English
Subjects:
Angiogenesis
Calcium-Binding Proteins - metabolism
Cancer
Cancer stroma
Carcinogenesis - metabolism
Cell Communication - physiology
Cell culture
Cell growth
Cell proliferation
Cells, Cultured
EGF Family of Proteins - metabolism
Endothelial cells
Exosomes
Exosomes - metabolism
Fibroblasts
Fibroblasts - metabolism
Flow cytometry
Gene expression
Humans
Lung Neoplasms - metabolism
Malignant mesothelioma
Mesothelioma
Mesothelioma - metabolism
Mesothelioma, Malignant
MicroRNAs
MicroRNAs - metabolism
miR-126
miRNA-based therapy
Proteins
Signal Transduction - physiology
Stromal cells
Toxicity
Tumors
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:MiR-126 has been shown to suppress malignant mesothelioma (MM) by targeting cancer-related genes without inducing toxicity or histopathological changes. Exosomes provide the opportunity to deliver therapeutic cargo to cancer stroma. Here, a tumour stromal model composed of endothelial cells (HUVECs), fibroblasts (IMR-90 cells), non-malignant mesothelial cells (Met-5A cells) and MM cells (H28 and MM-B1 cells) was used. The cells were treated with exosomes from HUVECs carrying endogenous (exo-HUVEC) and enriched miR-126 (exo-HUVECmiR−126), and the uptake/turnover of exosomes; miR-126 distribution within the stroma; and effect of miR-126 on cell signalling, angiogenesis and cell proliferation were evaluated. Based on the sensitivity of MM cells to exo-HUVEC miR-126 treatment, miR-126 was distributed differently across stromal cells. The reduced miR-126 content in fibroblasts in favour of endothelial cells reduced angiogenesis and suppressed cell growth in an miR-126-sensitive environment. Conversely, the accumulation of miR-126 in fibroblasts and the reduced level of miR-126 in endothelial cells induced tube formation in an miR-126-resistant environment via VEGF/EGFL7 upregulation and IRS1-mediated cell proliferation. These findings suggest that transfer of miR-126 via HUVEC-derived exosomes represents a novel strategy to inhibit angiogenesis and cell growth in MM. [Display omitted] •Exosome derived endothelial cells efficiently transfer miR-126 to the recipient stroma cells.•The internalised miR-126 is sorted and released via exosomes, which can be taken up by the cells themselves.•The distribution of exosomal transferred miR-126 among cells in a stroma model affect vessel formation and tumorigenesis.•Stromal fibroblasts orchestrated vessel formation by modulating miR-126-induced EGFL7 and VEGF expression.•Exosomal transfer of miR-126 inhibited cell growth via IRS1-AKT-MAPK pathway.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2019.08.001