In vivo gene delivery by embryonic-stem-cell-derived astrocytes for malignant gliomas
Mahmud Uzzaman1, Gordon Keller, Isabelle M Germano
1Department of neurosurgeruy, Mount Sinai School of Medicine, New York, NY 10029 USA.
Abstract:
The treatment of malignant gliomas with current therapies remains a challenge in neurooncology. Our recent work showed that embryonic stem cell (ESC)-derived astrocytes conditionally expressing genes can be used to induce apoptosis in malignant glioma cells in vitro. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene has been shown to induce apoptosis in a variety of tumor cells, including gliomas. The aim of this study was to assess the proapoptotic effects of transgenic TRAIL delivered by ESC-derived astrocytes on malignant gliomas in vivo. Malignant glioma A172 cells were used to induce heterotopic xenografts in nude mice. ESC-derived astrocytes conditionally expressing TRAIL were injected into the xenografts. TRAIL expression was documented in the malignant glioma xenografts by reverse transcription PCR and immunohistochemistry after external gene induction. A significant reduction in tumor volume occurred 48 h after a single injection (14%) and double injections (31%) in the experimental groups. Terminal dUTP nick end labeling (TUNEL) revealed abundant apoptotic tumor cells in the experimental groups. Seven days after injection, the tumor had undergone severe necrosis, with only scattered residual tumor cells at the periphery. Death receptor DR4 expression increased significantly in the experimental groups compared with controls. Our data suggest that ESC-derived astrocytes conditionally expressing TRAIL should be considered as vectors to deliver gene therapy for malignant gliomas.
Insights
Embryonic stem cell-derived astrocytes engineered to express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively reduced malignant glioma tumor volume and induced apoptosis in vivo.
Area of Science:
- Neuro-oncology
- Cancer Gene Therapy
- Stem Cell Biology
Background:
- Malignant gliomas are challenging to treat with current therapies.
- Embryonic stem cell (ESC)-derived astrocytes can induce apoptosis in glioma cells.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells.
Purpose of the Study:
- To evaluate the in vivo proapoptotic effects of transgenic TRAIL delivered by ESC-derived astrocytes on malignant gliomas.
- To assess the efficacy of this gene therapy approach in a xenograft model.
Main Methods:
- Malignant glioma A172 cells were used to create heterotopic xenografts in nude mice.
- ESC-derived astrocytes conditionally expressing TRAIL were injected into the xenografts.
- TRAIL expression, tumor volume, apoptosis (TUNEL), and death receptor DR4 expression were analyzed.
Main Results:
- Significant reduction in tumor volume (14% single, 31% double injection) was observed.
- Abundant apoptotic tumor cells and severe tumor necrosis were detected.
- Increased death receptor DR4 expression in experimental groups compared to controls.
Conclusions:
- ESC-derived astrocytes conditionally expressing TRAIL demonstrate significant proapoptotic effects on malignant gliomas in vivo.
- This approach shows promise as a gene therapy vector for malignant gliomas.
