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Targeting the tumor necrosis factor-related apoptosis-inducing ligand path in neuroblastoma
Xuezhong Yang1, Carol J Thiele
1Cell and Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 10 Center Dr., Bethesda, MD 20892, USA.
Abstract:
The identification of the tumor necrosis factor (TNF) superfamily member TNF-related apoptosis-inducing ligand (TRAIL) a few years ago generated considerable enthusiasm for it as a potential cancer therapeutic agent. This is because TRAIL shows potent apoptosis inducing activity in a wide spectrum of transformed cell lines but not in cell lines derived from normal tissue origin. As the details in the signal transduction pathway of TRAIL-induced apoptosis are clarified, various defects of TRAIL pathway have been identified in TRAIL resistant cancer cells. Neuroblastoma is the most common extracranial solid tumor in children and those with a poor prognosis require more sensitive therapies. Unlike other cancer cells, most neuroblastoma cell lines are resistant to TRAIL induced apoptosis and the resistance correlates with caspase 8 deficiency, which is attributed to the methylation of the gene. Interferon (IFN)-gamma induces caspase 8 expression in most neuroblastoma cell lines regardless of the methylation status but fails to sensitize most NB to TRAIL. Further analysis indicates a TRAIL receptor deficiency contributes to TRAIL resistance in NB. Multiple lesions suggest that this path may play an important role in tumorigenesis and/ or evasion from therapies. Furthermore it indicates that the clinical application of TRAIL in NB will require a multi-modality approach. Important questions remain unanswered: How does IFN-gamma induce caspase 8 and why is the induction heterogeneous? How to stimulate the caspase 8 induction in cells that fail to respond to IFN-gamma? How to target other TRAIL pathway lesions with the clinically feasible approaches?
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise as a cancer therapeutic. However, neuroblastoma resistance to TRAIL is linked to caspase 8 deficiency and TRAIL receptor issues, necessitating combination therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The tumor necrosis factor (TNF) superfamily member, TNF-related apoptosis-inducing ligand (TRAIL), is a promising cancer therapeutic due to its selective apoptosis-inducing activity in cancer cells.
- TRAIL resistance in cancer cells is often associated with defects in its signal transduction pathway, including caspase 8 deficiency and TRAIL receptor issues.
- Neuroblastoma, a common childhood cancer with poor prognosis, exhibits significant resistance to TRAIL-induced apoptosis.
Purpose of the Study:
- To investigate the mechanisms underlying TRAIL resistance in neuroblastoma.
- To explore the role of caspase 8 deficiency and interferon-gamma (IFN-gamma) in TRAIL resistance.
- To identify potential therapeutic strategies for overcoming TRAIL resistance in neuroblastoma.
Main Methods:
- Analysis of TRAIL-induced apoptosis in neuroblastoma cell lines.
- Investigation of caspase 8 expression and its regulation by gene methylation and IFN-gamma.
- Assessment of TRAIL receptor expression and its contribution to resistance.
Main Results:
- Most neuroblastoma cell lines are resistant to TRAIL, correlating with caspase 8 deficiency due to gene methylation.
- IFN-gamma can induce caspase 8 expression in neuroblastoma cells but does not consistently sensitize them to TRAIL.
- TRAIL receptor deficiency was identified as another factor contributing to TRAIL resistance in neuroblastoma.
Conclusions:
- TRAIL resistance in neuroblastoma is multifactorial, involving caspase 8 deficiency and TRAIL receptor defects.
- Clinical application of TRAIL for neuroblastoma will likely require combination therapies targeting multiple lesions in the TRAIL pathway.
- Further research is needed to understand IFN-gamma's heterogeneous effects on caspase 8 induction and to develop strategies for overcoming resistance in non-responsive cells.