Targeting different types of human meningioma and glioma cells using a novel adenoviral vector expressing GFP-TRAIL fusion protein from hTERT promoter

Abstract

ObjectiveThe objective of this study was to evaluate the anti-tumor effects of Ad/gTRAIL (an adenoviral vector in which expression of GFP and TRAIL is driven by a human telomerase reverse transcriptase promoter, hTERT) on malignant meningiomas and gliomas.BackgroundGliomas and meningiomas are the two most common types of human brain tumors. Currently there is no effective cure for recurrent malignant meningiomas or for gliomas. Ad/gTRAIL has been shown to be effective in killing selected lung, colon and breast cancer cells, but there have been no studies reporting its antitumor effects on malignant meningiomas. Therefore, we tested the antitumor effect of Ad/gTRAIL for the first time in human malignant meningioma and glioma cell lines, and in intracranial M6 and U87 xenografts.MethodsMaterials and Methods: Human malignant meningioma and glioma cells were infected with adenoviruses, Ad/gTRAIL and Ad/CMV-GFP. Cell viability was determined by proliferation assay. FACS analysis and quantification of TRAIL were used to measure apoptosis in these cells. We injected Ad/gTRAIL viruses in intracranial M6 and U87 xenografts, and measured the brain tumor volume, quantified apoptosis by TUNEL assay in the brain tumor tissue.ResultsOur studies demonstrate that in vitro/in vivo treatment with Ad/gTRAIL virus resulted in significant increase of TRAIL activity, and elicited a greater tumor cell apoptosis in malignant brain tumor cells as compared to treatment with the control, Ad/CMV-GFP virus without TRAIL activity.ConclusionsWe showed for the first time that adenovirus Ad/gTRAIL had significant antitumor effects against high grade malignant meningiomas as well as gliomas. Although more work needs to be done, our data suggests that Ad/gTRAIL has the potential to be useful as a tool against malignant brain tumors.

Human telomerase reverse-transcriptase promoter-controlled and herpes simplex virus thymidine kinase-armed adenoviruses for renal cell carcinoma treatment

“…Ad-hTERT-EGFP infected 786-0 cells effectively at the same MOI, but did not infect MRC-5 cells at any MOI, suggesting that the hTERT-mediated gene expression is highly tumor-specific. These findings are consistent with the results published by previous reports 26,27…”

High Incidence of ActivatingTERTPromoter Mutations in Meningiomas Undergoing Malignant Progression

“…One of these alterations is telomerase activation. Telomerase activation has been demonstrated by telomere repeat amplification protocol (TRAP) assay or quantitative polymerase chain reaction (PCR) of TERT in about 10% of grade I meningiomas, 50% of grade II and around 95% of grade III meningiomas . Nevertheless, mechanisms underlying telomerase activation remain unknown in meningiomas.…”

Bortezomib Sensitizes Primary Meningioma Cells to TRAIL-Induced Apoptosis by Enhancing Formation of the Death-Inducing Signaling Complex

“…However, TRAIL sensitivity could be restored in all of these tumor entities by combinatorial treatment of TRAIL with the proteasome inhibitor bortezomib, which was associated with a robust upregulation of TRAIL-R1 and/or TRAIL-R2 (14,18,25). The first hint for the antitumor activity of TRAIL in meningiomas came from studies with adenoviral transduction of TRAIL into human meningioma cells (27). Thus, we decided to evaluate soluble TRAIL as a therapeutic option for meningiomas by investigating freshly isolated primary tumor cells.…”