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Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

Gene Therapy volume 21, pages 874–887 (2014)Cite this article

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Abstract

Mesenchymal stromal cells (MSC) can be exploited as cellular delivery vehicles for the enzymes converting non-toxic prodrugs to toxic substances. Because of their inherent chemoresistance, they exert potent bystander and antitumor effect. Here we show that the human adipose tissue-derived MSC expressing fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (CD-MSC) in combination with 5-fluorocytosine (5FC) mediated a long-term tumor-free survival in the 83.3% of tumor-bearing animals. CD-MSC/5FC treatment induced cytotoxicity against model human melanoma cells EGFP-A375. Only 4% of the therapeutic CD-MSC cells eliminated >98.5% of the tumor cells in vitro. Long-term tumor-free survival was confirmed in 15 out of the 18 animals. However, repeatedly used CD-MSC/5FC therapeutic regimen generated more aggressive and metastatic variant of the melanoma cells EGFP-A375/Rel3. These cells derived from the refractory xenotransplants exhibited increased resistance to the CD-MSC/5FC treatment, altered cell adhesion, migration, tumorigenic and metastatic properties. However, long-term curative effect was achieved by the augmentation of the CD-MSC/5FC regimen along with the inhibition of c-Met/hepatocyte growth factor signaling axis in this aggressive melanoma derivative. In summary, the CD-MSC/5FC regimen can be regarded as a very effective antitumor approach to achieve long-term tumor-free survival as demonstrated on a mouse model of aggressive human melanoma xenografts.

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Acknowledgements

We thank M Dubrovcakova and V Frivalska for the excellent technical assistance. We acknowledge M Cihova for the help with manuscript editing and language corrections. The support and help with the data interpretation from M Mego, MD, PhD is highly appreciated. This work was supported by the Slovak Research and Development Agency under the contract No. APVV-0230-11 (to LK) and APVV-0052-12 (to MM), Scientific Grant Agency VEGA grant No. 2/0088/11 (to LK) and 2/0171/13 (to MM). The expression analysis, fluorimetric measurements and live-cell kinetic imaging was co-financed by the Cancer Research Foundation funds WAC2003, RFL2009 and RFL2012.

AUTHOR CONTRIBUTIONS

Conception, design and development of methodology: LK; data acquisition: LK, SS, LD, RB and MM; analysis and data interpretation: LK and MM; writing of the manuscript and review: LK.

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia

    L Kucerova, S Skolekova, L Demkova, R Bohovic & M Matuskova

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  1. L Kucerova
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  2. S Skolekova
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  3. L Demkova
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  4. R Bohovic
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Correspondence to L Kucerova.

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Kucerova, L., Skolekova, S., Demkova, L. et al. Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model. Gene Ther 21, 874–887 (2014). https://doi.org/10.1038/gt.2014.66

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