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TRAIL-transduced multipotent mesenchymal stromal cells (TRAIL-MSC) overcome TRAIL resistance in selected CRC cell lines in vitro and in vivo

Cancer Gene Therapy volume 18, pages 229–239 (2011)Cite this article

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Abstract

Tumor-integrating multipotent mesenchymal stromal cells (MSC) expressing transgenes with anti-tumor activity may serve as vehicles for tumor therapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents such a factor; however, TRAIL-resistant tumor cells exist. Based on our previous work, here we investigated whether MSC with lentiviral TRAIL expression (TRAIL-MSC) inhibit the growth of TRAIL-resistant colorectal carcinoma (CRC) cells. Our data show that TRAIL-MSC induce apoptosis in selected TRAIL-resistant CRC cell lines and effectively inhibit the growth of TRAIL-resistant HCT8 cells. This sensitization to TRAIL-induced apoptosis required the presence of MSC-expressed TRAIL. However, for the first time we show that selected CRC cells are resistant to TRAIL-MSC. In the cell line HT29, this resistance could be overcome by concomitant subapoptotic genotoxic damage in vitro. However, such sensitization was not achieved in vivo as treatment of mixed HT29/TRAIL-MSC xenografts with 5-FU rather resulted in enhanced growth. Taken together, our data prove that TRAIL-MSC overcome TRAIL resistance in selected CRC cells through direct intercellular interaction and may, therefore, represent a clinical tool to overcome TRAIL resistance. However, such potential clinical use requires further preclinical studies as our data also prove that TRAIL-MSC-resistant CRC cells exist. Our data add to the notion that TRAIL resistance of CRC cells is conferred by different mechanisms.

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Acknowledgements

We are grateful to the donors who consented the use of their bone marrow aspirates. We thank Professor Dr K Maeder, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg for the non-invasive in vivo multispectral fluorescence imaging. The study was supported in part by grants from the Federal State of Saxonia-Anhalt and the German Ministry of Education and Research through the Wilhelm-Roux-Program at the Medical Faculty of the Martin-Luther-University Halle-Wittenberg (NBL-3 program 1/09, 3/15, 6/08, 3/27) as well by a grant from the Federal State of Saxonia-Anhalt (FKZ: 3646A/0907).

Author contributions: LPM, JL and TM designed the study; LPM, JL, MW, KN, HC and TM performed the research; LPM, JL, HC and TM controlled and analyzed data; LPM, JL and TM wrote the paper.

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  1. L P Mueller and J Luetzkendorf: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine IV, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany

    L P Mueller, J Luetzkendorf, M Widder, K Nerger, H Caysa & T Mueller

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  1. L P Mueller
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Correspondence to L P Mueller.

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Competing interests

Dr LP Mueller, J Luetzkendorf and Dr T Mueller have filed a patent on the lentiviral TRAIL-MSC described in this report. All other authors, M Widder, K Nerger and H Caysa, have no conflict of interest to declare.

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Mueller, L., Luetzkendorf, J., Widder, M. et al. TRAIL-transduced multipotent mesenchymal stromal cells (TRAIL-MSC) overcome TRAIL resistance in selected CRC cell lines in vitro and in vivo. Cancer Gene Ther 18, 229–239 (2011). https://doi.org/10.1038/cgt.2010.68

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