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In vivo imaging of S-TRAIL-mediated tumor regression and apoptosis
Khalid Shah1, Ching-Hsuan Tung, Xandra O Breakefield
1Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. kshah@helix.mgh.harvard.edu
Abstract:
Therapeutic proteins with specific effector functions play an increasingly important role in drug therapy. For example, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) predominantly kills cancer cells, while sparing normal cells. Here, we report the use of a secreted version of TRAIL as a therapeutic protein that induces apoptosis and kills surrounding cells in vivo, thus resulting in the dramatic reduction of glioma burden in mouse tumor models. Using a caspase-3-activatable aminoluciferin, we were able to show the induction of apoptosis specifically in S-TRAIL vector-infected gliomas. We also show that S-TRAIL-mediated apoptosis and resulting changes in tumor burden can be imaged in the same animal by dual-substrate bioluminescence imaging. The use of S-TRAIL as a therapeutic protein and the ability to image noninvasively both apoptosis and any other cellular events in real time have important clinical implications.
Insights
Secreted tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively reduces glioma burden in mice by inducing apoptosis in cancer cells. This therapeutic approach allows for real-time, noninvasive imaging of treatment response.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Therapeutic proteins with specific effector functions are crucial in modern drug therapy.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, sparing normal cells.
- Gliomas are aggressive brain tumors with limited effective treatment options.
Purpose of the Study:
- To investigate the therapeutic potential of a secreted version of TRAIL (S-TRAIL) for glioma treatment.
- To demonstrate S-TRAIL's ability to induce apoptosis and reduce tumor burden in vivo.
- To establish a method for noninvasive imaging of S-TRAIL-mediated apoptosis and treatment response.
Main Methods:
- Utilized a secreted TRAIL (S-TRAIL) protein as a therapeutic agent in mouse glioma models.
- Employed a caspase-3-activatable aminoluciferin to detect apoptosis specifically in S-TRAIL-treated gliomas.
- Applied dual-substrate bioluminescence imaging to monitor apoptosis and changes in tumor burden in real time within the same animal.
Main Results:
- S-TRAIL treatment led to a dramatic reduction in glioma burden in mouse models.
- Apoptosis was specifically induced in S-TRAIL vector-infected gliomas, confirmed by aminoluciferin imaging.
- Dual-substrate bioluminescence imaging successfully visualized S-TRAIL-mediated apoptosis and tumor burden changes in vivo.
Conclusions:
- Secreted TRAIL (S-TRAIL) is a promising therapeutic protein for inducing apoptosis and reducing glioma burden.
- Noninvasive, real-time imaging of apoptosis and cellular events offers significant clinical implications for monitoring treatment efficacy.
- The combination of S-TRAIL therapy and bioluminescence imaging presents a novel strategy for glioma management.
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