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Engineered herpes simplex viruses efficiently infect and kill CD133+ human glioma xenograft cells that express CD111

  • Laboratory Investigation - Human/animal tissue
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Abstract

Oncolytic herpes simplex viruses (HSV) hold promise for therapy of glioblastoma multiforme (GBM) resistant to traditional therapies. We examined the ability of genetically engineered HSV to infect and kill cells that express CD133, a putative marker of glioma progenitor cells (GPC), to determine if GPC have an inherent therapeutic resistance to HSV. Expression of CD133 and CD111 (nectin-1), the major entry molecule for HSV, was variable in six human glioma xenografts, at initial disaggregation and after tissue culture. Importantly, both CD133+ and CD133− populations of glioma cells expressed CD111 in similar relative proportions in five xenografts, and CD133+ and CD133− glioma cell subpopulations were equally sensitive to killing in vitro by graded dilutions of wild-type HSV-1(F) or several different γ134.5-deleted viruses. GPC did not display an inherent resistance to HSV. While CD111 expression was an important factor for determining sensitivity of glioma cells to HSV oncolysis, it was not the only factor. Our findings support the notion that HSV will not be able to effectively enter, infect, and kill cells in tumors that have low CD111 expression (<20%). However, virotherapy with HSV may be very effective against CD111+ GPC resistant to traditional therapies.

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Acknowledgments

We thank Drs. C.D. James, J. Sarkaria and D.D. Bigner for the gifts of human glioma xenograft lines used in this study. We thank Dr. B. Roizman for the gift of some of the HSV strains used in this work. We thank Enid Keyser for her expertise on FACS analyses, which were performed at the UAB Flow Cytometry shared facility. This research was supported in part by the Dixon Fellowship (GKF), and NIH grants CA097247 (GYG, KAC, JNP, JMM) and CA071933 (JMM, JNP, GYG).

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Authors and Affiliations

  1. Brain Tumor Research Program, Department of Pediatrics, University of Alabama at Birmingham, 1046 Tinsley Harrison Tower, 1900 University Boulevard, Birmingham, AL, 35294-0006, USA

    Gregory K. Friedman, Kevin A. Cassady, Jacqueline N. Parker & James M. Markert

  2. Department of Surgery, Division of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, 35294-0006, USA

    Catherine P. Langford, Jennifer M. Coleman, James M. Markert & G. Yancey Gillespie

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  1. Gregory K. Friedman
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  2. Catherine P. Langford
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  3. Jennifer M. Coleman
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  7. G. Yancey Gillespie
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Correspondence to Gregory K. Friedman.

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Friedman, G.K., Langford, C.P., Coleman, J.M. et al. Engineered herpes simplex viruses efficiently infect and kill CD133+ human glioma xenograft cells that express CD111. J Neurooncol 95, 199–209 (2009). https://doi.org/10.1007/s11060-009-9926-0

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