Oncolytic Herpes Simplex Virus Counteracts the Hypoxia-Induced Modulation of Glioblastoma Stem-Like Cells

Stem cells translational medicine - Tập 1 Số 4 - Trang 322-332 - 2012
Donatella Sgubin1,2, Hiroaki Wakimoto1, Ryuichi Kanai1, Samuel D. Rabkin1, Robert L. Martuza1
1Department of Neurosurgery, Brain Tumor Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
2Neurosurgery Department, Padova University, Padova, Italy

Tóm tắt

Abstract Glioblastoma (GBM), a fatal malignant brain tumor, contains abundant hypoxic regions that provide a “niche” to promote both the maintenance and enrichment of glioblastoma stem-like cells (GSCs) and confer resistance to chemo- and radiotherapy. Since GSCs, with an ability to resist conventional therapies, may be responsible for tumor recurrence, targeting GSCs located in such a hypoxic environment may be critical to improving the therapeutic outcome for GBM patients. Oncolytic viral therapies have been tested in the clinic as a promising therapeutic approach for GBM. In this study, we analyzed and compared the therapeutic effects of oncolytic herpes simplex virus (oHSV) type 1 G47Δ (γ34.5−ICP6−LacZ+α47−) in patient-derived GSCs under normoxia (21% oxygen) and hypoxia (1% oxygen). GSCs cultured in hypoxia showed an increased ability to form neurospheres and expressed higher levels of the putative stem cell marker CD133 compared with GSCs cultured in normoxia. G47Δ exhibited a comparable ability to infect, replicate, and kill GSCs in normoxia and hypoxia in vitro. Importantly, G47Δ could counteract hypoxia-mediated enhancement of the stem-like properties of GSCs, inhibiting their self-renewal and stem cell marker expression. Using orthotopic human GSC xenografts in mice, we demonstrated that intratumoral injection of G47ΔUs11fluc, a newly developed G47Δ derivative that expresses firefly luciferase driven by a true late viral promoter, led to an equivalent frequency of viral infection and replication in hypoxic and nonhypoxic tumor areas. These findings suggest that oHSV G47Δ represents a promising therapeutic strategy to target and kill GSCs, not only in normoxic areas of GBM but also within the hypoxic niche.

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Stem cells translational medicine

Tập 1 Số 4

322-332

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