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Real-time imaging of TRAIL-induced apoptosis of glioma tumors in vivo

Oncogene volume 22, pages 6865–6872 (2003)Cite this article

20 February 2024 Editor's note: Readers are alerted that concerns have been raised regarding the reliability of data presented in this article. Further editorial action will be taken if appropriate once the investigation into the concerns is complete and all parties have been given an opportunity to respond in full.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in neoplastic cells. While many previous studies have been performed in cell culture, the delivery and efficiency of TRAIL variants in vivo is less well established. Using dual substrate/reporter bioluminescence imaging (Fluc: firefly luciferase – luciferin and Rluc: Renilla luciferase – coelenterazine), we tested the efficacy of TRAIL using replication-deficient herpes simplex virus (HSV) type 1 amplicon vectors in gliomas. The cDNA for complete TRAIL and the extracellular domain of TRAIL (aa 114–281) were cloned into HSV amplicons and packaged into helper virus-free vectors. Both forms of TRAIL induced similar degrees of apoptosis in human glioma cells (Gli36) in culture within 24 h of infection with TRAIL amplicon vectors. Growth of tumors stably transfected with Fluc (Gli36fluc+) was readily monitored in vivo by bioluminescence imaging following luciferin administration. HSV amplicon vectors bearing the genes for TRAIL and Rluc injected directly into Gli36fluc+-expressing subcutaneous gliomas revealed peak Rluc activity 36 h after intratumoral injection as determined by coelenterazine injection followed by imaging. TRAIL-treated gliomas regressed in size over a period of 4 weeks as compared to the mock-injected gliomas. These results show the efficacy of vector delivered TRAIL in treating tumors in vivo and offer a unique way to monitor both gene delivery and efficacy of TRAIL-induced apoptosis in tumors in vivo in real time by dual enzyme substrate (Rluc/Fluc) imaging.

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  • 20 February 2024

    Editor's note: Readers are alerted that concerns have been raised regarding the reliability of data presented in this article. Further editorial action will be taken if appropriate once the investigation into the concerns is complete and all parties have been given an opportunity to respond in full.

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Acknowledgements

We thank Sara Camp for helping with viral DNA preparations and Deb Schuback for interesting discussions. We also thank Dr Edward Graves for providing us with the image analysis program and its regular upgrades and Dr Vasilis Nziachristos for help with the imaging system installation and CCD camera calibration. This work is supported in part by American Brain Tumor Association grant, Gene therapy for brain tumors (GTBT) CA6924 grant, a P50 center grant (CA86355), Goldhirsh Medical Foundation of Massachusetts and small animal imaging resource grant (SAIRG) (R24-CA92782).

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Authors and Affiliations

  1. Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Khalid Shah, Yi Tang & Ralph Weissleder

  2. Department of Neurology Massachusetts General Hospital, Molecular Neurogenetics Unit, Harvard Medical School, Boston, MA, USA

    Khalid Shah & Xandra Breakefield

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  1. Khalid Shah
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Correspondence to Khalid Shah.

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Shah, K., Tang, Y., Breakefield, X. et al. Real-time imaging of TRAIL-induced apoptosis of glioma tumors in vivo. Oncogene 22, 6865–6872 (2003). https://doi.org/10.1038/sj.onc.1206748

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