Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes

• Published in: International journal of cancer 2019-02, Vol.144 (4), p.897-908
• Main Authors: Altanerova, Ursula, Jakubechova, Jana, Benejova, Katarina, Priscakova, Petra, Pesta, Martin, Pitule, Pavel, Topolcan, Ondrej, Kausitz, Juraj, Zduriencikova, Martina, Repiska, Vanda, Altaner, Cestmir
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Antimetabolites, Antineoplastic - metabolism; Antimetabolites, Antineoplastic - pharmacology; Brain tumors; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cytosine; Cytosine deaminase; Cytosine Deaminase - genetics; Cytosine Deaminase - metabolism; Exosomes; Exosomes - genetics; Exosomes - metabolism; Flucytosine - metabolism; Fluorouracil - metabolism; Fluorouracil - pharmacology; Fungal Proteins - genetics; Fungal Proteins - metabolism; Fusion protein; Gene directed enzyme prodrug therapy; Gene therapy; Genes, Transgenic, Suicide - genetics; Genetic Therapy - methods; Humans; Intracellular; Medical research; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Mesenchyme; MicroRNAs; miRNA; mRNA; MSC suicide gene exosomes; Pentosyltransferases - genetics; Pentosyltransferases - metabolism; Prodrugs - metabolism; Stem cells; suicide gene; Suicide genes; Tissues; Tumor cells; Tumors; Uracil; Yeasts - genetics; Yeasts - metabolism
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.31792

The natural behavior of mesenchymal stem cells (MSCs) and their exosomes in targeting tumors is a promising approach for curative therapy. Human tumor tropic mesenchymal stem cells (MSCs) isolated from various tissues and MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase suicide fusion gene (yCD::UPRT‐MSCs) released exosomes in conditional medium (CM). Exosomes from all tissue specific yCD::UPRT‐MSCs contained mRNA of the suicide gene in the exosome's cargo. When the CM was applied to tumor cells, the exosomes were internalized by recipient tumor cells and in the presence of the prodrug 5‐fluorocytosine (5‐FC) effectively triggered dose‐dependent tumor cell death by endocytosed exosomes via an intracellular conversion of the prodrug 5‐FC to 5‐fluorouracil. Exosomes were found to be responsible for the tumor inhibitory activity. The presence of microRNAs in exosomes produced from naive MSCs and from suicide gene transduced MSCs did not differ significantly. MicroRNAs from yCD::UPRT‐MSCs were not associated with therapeutic effect. MSC suicide gene exosomes represent a new class of tumor cell targeting drug acting intracellular with curative potential. What's new? Mesenchymal stem cells (MSC) migrate toward tumors and are currently being exploited as conduits for targeted cancer treatment. The authors engineered MSCs to express a suicide gene (yeast cytosine deaminase::uracil phosphoribosyl Transferase) converting a prodrug (5‐fluorocytosine) into a cytotoxic cancer treatment (5‐fluorouracil). They find mRNAs of the suicide gene secreted in exosomes from MSCs and the exosomes to exhibit cytotoxic effects in the presence of prodrug. This study adds MSC‐derived exosomes to the list of targeted cancer drug delivery approaches.