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Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes |
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| Authors: | Ursula Altanerova Jana Jakubechova Katarina Benejova Petra Priscakova Martin Pesta Pavel Pitule Ondrej Topolcan Juraj Kausitz Martina Zduriencikova Vanda Repiska Cestmir Altaner |
| Affiliation: | 1. St. Elisabeth Cancer Institute, Stem Cell Preparation Department, Bratislava, Slovakia;2. Faculty of Medicine, Institute of Medical Biology, Genetics and Clinical Genetics, University Hospital Bratislava, Comenius University in Bratislava, Bratislava, Slovakia;3. Department of Biology, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic Laboratory of tumor biology, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic University Hospital in Pilsen, Department of Nuclear Medicine - Immunoanalytic Laboratory, Pilsen, Czech Republic;4. Laboratory of tumor biology, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic;5. University Hospital in Pilsen, Department of Nuclear Medicine - Immunoanalytic Laboratory, Pilsen, Czech Republic;6. Cancer Research Institute, Biomedical Center, Slovak Academy of Sciences, Bratislava, Slovakia |
| Abstract: | 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. |
| Keywords: | mesenchymal stem cells suicide gene MSC suicide gene exosomes Gene directed enzyme prodrug therapy |