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AAV-encoded expression of TRAIL in experimental human colorectal cancer leads to tumor regression

Gene Therapy volume 11, pages 534–543 (2004)Cite this article

Abstract

Gene transfer vectors based on the adeno-associated virus (AAV) are used for various experimental and clinical therapeutic approaches. In the present study, we demonstrate the utility of rAAV as a tumoricidal agent in human colorectal cancer. We constructed an rAAV vector that expresses tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) and used it to transduce human colorectal cancer cells. TRAIL belongs to the TNF superfamily of cytokines that are involved in various immune responses and apoptotic processes. It has been shown to induce cell death specifically in cancer cells. Transduction with AAV.TRAIL gave rise to rapid expression of TRAIL, followed by induction of apoptosis, which could be inhibited by the caspase inhibitor z-VAD.fmk, in several human colon cancer cell lines. The apoptotic mechanism included activation of caspase-3, as well as cytochrome c release from mitochondria. The outgrowth of human colorectal tumors grown in mice was completely blocked by transduction with AAV.TRAIL in vitro, while in vivo transduction significantly inhibited the growth of established tumors. AAV vectors could provide a safe method of gene delivery and offer a novel method of using TRAIL as a therapeutic protein.

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Acknowledgements

This study was supported by the Deutsche Forschungsgemeinschaft (DFG) within their Emmy Noether Program (ZW 60/2-1) and the Scottish Hospital Endowments Research Trust (SHERT) through a travel grant (RMZ). The project was initiated at the University of Edinburgh, Department of Oncology and the initial work was carried out at Tulane Medical School, Department of Pathology.

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Authors and Affiliations

  1. University Children's Hospital, Germany

    A Mohr & K-M Debatin

  2. Division of Gene Therapy and Interdisciplinary Clinical Research Center, University of Ulm, Ulm, Germany

    G Henderson & RM Zwacka

  3. Department of Pathology and Laboratory Medicine, Tulane University Medical Center, New Orleans, LA, USA

    L Dudus & KJ Fisher

  4. German Cancer Research Center, Molecular Oncology/Pediatrics, Heidelberg, Germany

    I Herr

  5. Center for Molecular Biology, Heidelberg, Germany

    T Kuerschner

  6. Institute for Diabetes Research, Munich, Germany

    H Weiher

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  1. A Mohr
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  2. G Henderson
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  3. L Dudus
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  4. I Herr
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  6. K-M Debatin
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  8. KJ Fisher
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  9. RM Zwacka
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Mohr, A., Henderson, G., Dudus, L. et al. AAV-encoded expression of TRAIL in experimental human colorectal cancer leads to tumor regression. Gene Ther 11, 534–543 (2004). https://doi.org/10.1038/sj.gt.3302154

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  • DOI: https://doi.org/10.1038/sj.gt.3302154

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