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Ectopic matrix metalloproteinase-9 expression in human brain tumor cells enhances oncolytic HSV vector infection

Gene Therapy volume 17, pages 1200–1205 (2010)Cite this article

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Abstract

Oncolytic herpes simplex virus (oHSV) vectors have shown promise in the treatment of patients with recurrent brain tumors although few complete responses have accrued. Impediments to effective therapy include limited vector distribution on delivery, a consequence of injected virion particle trapping in the tumor extracellular matrix (ECM). To enhance virus delivery and spread, we investigated the use of the matrix metalloproteinase-9 (MMP-9) as a means to degrade collagen type IV, a major component of the ECM and basement membranes of gliomas that is absent in normal brain tissue. SK-N-AS neuroblastoma cells were transduced for constitutive, elevated expression of MMP-9, which did not enhance tumor cell migration in vitro or tumor progression in a murine xenograft brain tumor model. MMP-9 expression improved the distribution and infection of oHSV vectors in spheroid model in vitro. Furthermore, MMP9 induced a vector infection over larger areas of brain tumors in vivo. These results suggest that vector delivery and distribution in vivo can be improved by compromising the ECM, potentially enhancing oncolytic efficacy.

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Acknowledgements

We thank Antonio Chiocca (Ohio State University) for MGH2, Hideho Okada (University of Pittsburgh) for cell lines, Lucia Mazzacurati and Adriana Forero for technical assistance and Bonnie Reinhart for valuable contributions to the article. This research was supported by NIH Grants nos. NS040923 and CA119298 (to JCG), and by a grant from the Copeland Foundation (to PG).

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Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    C-S Hong, J B Cohen & J C Glorioso

  2. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    W Fellows, A Niranjan & P Grandi

  3. Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    S Alber & S Watkins

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  1. C-S Hong
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  2. W Fellows
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Correspondence to P Grandi.

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Hong, CS., Fellows, W., Niranjan, A. et al. Ectopic matrix metalloproteinase-9 expression in human brain tumor cells enhances oncolytic HSV vector infection. Gene Ther 17, 1200–1205 (2010). https://doi.org/10.1038/gt.2010.66

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