In vivo gene delivery by embryonic-stem-cell-derived astrocytes for malignant gliomas.
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.
Uzzaman
Mahmud
M
Department of neurosurgeruy, Mount Sinai School of Medicine, New York, NY 10029 USA.
Keller
Gordon
G
Germano
Isabelle M
IM
D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D053595:Embryonic Stem Cells / Q000502:physiology*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005910:Glioma / Q000235:genetics / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D023822:Tissue Engineering; D023041:Xenograft Model Antitumor Assays
D053221:TNF-Related Apoptosis-Inducing Ligand