Journal
CELLS
Volume 11, Issue 23, Pages -Publisher
MDPI
DOI: 10.3390/cells11233828
Keywords
extracellular vesicles; metastatic uveal melanoma; hepatic stellate cells; endothelial cells
Categories
Funding
- Vision Health Research Network (VHRN)
- Fonds de recherche du Quebec-Sante (FRQS)
- International Networking Program
- Fondation du CHU de Quebec [IS122387]
- Fondation des maladies de l'oeil [85340]
- Canada Foundation for Innovation [85406]
- VHRN [32808]
- FRQS
- Mitacs
- Fondation du CHU de Quebec-Desjardins
- Centre de recherche sur le cancer de l'Universite Laval
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This study investigates the effects of extracellular vesicles (EVs) released by uveal melanoma (UM) cells on stellate and endothelial cells in the tumor microenvironment. The findings show that UM-derived EVs lead to increased contractility in hepatic stellate cells and promote the formation of capillary-like networks in endothelial cells.
Uveal melanoma (UM) is the most common primary intraocular tumor and often spreads to the liver. Intercellular communication though extracellular vesicles (EVs) plays an important role in several oncogenic processes, including metastasis, therapeutic resistance, and immune escape. This study examines how EVs released by UM cells modify stellate and endothelial cells in the tumor microenvironment. The surface markers, and the concentration and size of EVs derived from UM cells or choroidal melanocytes were characterized by high-resolution flow cytometry, electron microscopy, and Western blotting. The selective biodistribution of EVs was studied in mice by fluorescence imaging. The activation/contractility of stellate cells and the tubular organization of endothelial cells after exposure to melanomic EVs were determined by traction force microscopy, collagen gel contraction, or endothelial tube formation assays. We showed that large EVs from UM cells and healthy melanocytes are heterogenous in size, as well as their expression of phosphatidylserine, tetraspanins, and Tsg101. Melanomic EVs mainly accumulated in the liver and lungs of mice. Hepatic stellate cells with internalized melanomic EVs had increased contractility, whereas EV-treated endothelial cells developed more capillary-like networks. Our study demonstrates that the transfer of EVs from UM cells leads to a pro-fibrotic and pro-angiogenic phenotype in hepatic stellate and endothelial cells.
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