In vivo Gene Delivery by embryonic stem cell-derived astrocytes for malignant gliomas

¹ Department of Neurosurgery, Mt. Sinai School of Medicine, New York, NY, USA
² Gene and Cell Medicine, Mt. Sinai School of Medicine, New York, NY, USA

^* To whom correspondence should be addressed. E-mail: isabelle.germano{at}mountsinai.org.

	Abstract

The treatment of malignant gliomas with current therapies remains a challenge in neuro-oncology. 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 is to assess the pro-apoptotic 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 RT-PCR and immunohistochemistry after external gene induction. A significant reduction in tumor volume occurred 48 hours after a single injection (14%) and double (31%) injections in the experimental groups. 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 to controls. Our data suggest that ESC-derived astrocytes conditionally expressing TRAIL should be considered as vectors to deliver gene therapy for malignant gliomas.

Key Words: astrocytes, embryonic stem cell, gene therapy, malignant glioma, TRAIL

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