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Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors

¹ Molecular Neurosurgery Laboratory, Brain Tumor Research Center, Department of Neurosurgery, ² Department of Pathology, ³ Molecular Neurotherapy and Imaging Laboratory, Center for Molecular Imaging Research, Department of Radiology, Department of Neurology, Massachusetts General Hospital, and ⁴ Department of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute/Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and ⁵ Center for Neuroregeneration Research, McLean Hospital, Harvard Medical School, Belmont, Massachusetts

Requests for reprints: Hiroaki Wakimoto, Brain Tumor Research Center, CPZN-3800, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114. Phone: 617-643-5987; Fax: 617-643-3422; E-mail: hwakimoto{at}partners.org.

Key Words: cancer stem cells • glioblastoma • oncolytic herpes simplex virus

Glioblastoma, the most malignant type of primary brain tumor, is one of the solid cancers where cancer stem cells have been isolated, and studies have suggested resistance of those cells to chemotherapy and radiotherapy. Here, we report the establishment of CSC-enriched cultures derived from human glioblastoma specimens. They grew as neurospheres in serum-free medium with epidermal growth factor and fibroblast growth factor 2, varied in the level of CD133 expression and very efficiently formed highly invasive and/or vascular tumors upon intracerebral implantation into immunodeficient mice. As a novel therapeutic strategy for glioblastoma-derived cancer stem–like cells (GBM-SC), we have tested oncolytic herpes simplex virus (oHSV) vectors. We show that although ICP6 (UL39)–deleted mutants kill GBM-SCs as efficiently as wild-type HSV, the deletion of 34.5 significantly attenuated the vectors due to poor replication. However, this was significantly reversed by the additional deletion of 47. Infection with oHSV G47 (ICP6^–, 34.5^–, 47^–) not only killed GBM-SCs but also inhibited their self-renewal as evidenced by the inability of viable cells to form secondary tumor spheres. Importantly, despite the highly invasive nature of the intracerebral tumors generated by GBM-SCs, intratumoral injection of G47 significantly prolonged survival. These results for the first time show the efficacy of oHSV against human GBM-SCs, and correlate this cytotoxic property with specific oHSV mutations. This is important for designing new oHSV vectors and clinical trials. Moreover, the new glioma models described in this study provide powerful tools for testing experimental therapeutics and studying invasion and angiogenesis. [Cancer Res 2009;69(8):3472–81]