Suicide-Gene-Modified Extracellular Vesicles of Human Primary Uveal Melanoma in Future Therapies

Suicide-Gene-Modified Extracellular Vesicles of Human Primary Uveal Melanoma in Future Therapies

Extracellular vesicles secreted from uveal melanoma (UM) cells are involved in the establishment of the premetastatic niche and display transforming potential for the formation of metastases, preferentially in the liver. In this study, we cultivated human primary UM cells and uveal melanoma-associat...

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Bibliographic Details
Main Authors: Jana Jakubechova, Bozena Smolkova, Alena Furdova, Lucia Demkova, Ursula Altanerova, Andreas Nicodemou, Tatiana Zeleznikova, Daniela Klimova, Cestmir Altaner
Format: Article
Language:English
Published: MDPI AG 2023-08-01
Series:International Journal of Molecular Sciences
Subjects:
primary uveal melanoma
transduction with suicide gene
therapeutic extracellular vesicles
gene-directed enzyme prodrug therapy
Online Access:https://www.mdpi.com/1422-0067/24/16/12957
Description
Summary:Extracellular vesicles secreted from uveal melanoma (UM) cells are involved in the establishment of the premetastatic niche and display transforming potential for the formation of metastases, preferentially in the liver. In this study, we cultivated human primary UM cells and uveal melanoma-associated fibroblasts in vitro to be transduced by infection with a retrovirus containing the suicide gene—fused yeast cytosine deaminase::uracil phospho-ribosyl transferase (<i>yCD::UPRT</i>). A homogenous population of <i>yCD::UPRT</i>-UM cells with the integrated provirus expressed the gene, and we found it to continuously secrete small extracellular vesicles (sEVs) possessing mRNA of the suicide gene. The <i>yCD::UPRT</i>-UM-sEVs were internalized by tumor cells to the intracellular conversion of the prodrug 5-fluorocytosine (5-FC) to the cytotoxic drug 5-fluorouracil (5-FU). The host range of the <i>yCD::UPRT</i>-UM-sEVs was not limited to UMs only. The <i>yCD::UPRT</i>-UM-sEVs inhibited the growth of the human cutaneous melanoma cell line A375 and uveal melanoma cell line MP38, as well as other primary UMs, to various extents in vitro. The <i>yCD::UPRT</i>-UM-sEVs hold the therapeutic and prophylactic potential to become a therapeutic drug for UM. However, the use of <i>yCD::UPRT</i>-UM-sEVs must first be tested in animal preclinical studies.
ISSN:1661-6596
1422-0067

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