title: Oncolytic herpes simplex virus counteracts the hypoxia-induced modulation of glioblastoma stem-like cells.
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.
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Donatella
authors.initials: D
authors.lastname: Sgubin
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kanai
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Rabkin
authors.forename: Robert L
authors.initials: RL
authors.lastname: Martuza
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy / Q000821:virology; D015687:Cell Hypoxia; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy / Q000821:virology; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000502:physiology*; D018139:Simplexvirus / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology*