Enhanced antitumor efficacy of an oncolytic herpes simplex virus expressing an endostatin-angiostatin fusion gene in human glioblastoma stem cell xenografts

PLoS One. 2014 Apr 22;9(4):e95872. doi: 10.1371/journal.pone.0095872. eCollection 2014.

Abstract

Viruses have demonstrated strong potential for the therapeutic targeting of glioblastoma stem cells (GSCs). In this study, the use of a herpes simplex virus carrying endostatin-angiostatin (VAE) as a novel therapeutic targeting strategy for glioblastoma-derived cancer stem cells was investigated. We isolated six stable GSC-enriched cultures from 36 human glioblastoma specimens and selected one of the stable GSCs lines for establishing GSC-carrying orthotopic nude mouse models. The following results were obtained: (a) VAE rapidly proliferated in GSCs and expressed endo-angio in vitro and in vivo 48 h and 10 d after infection, respectively; (b) compared with the control gliomas treated with rHSV or Endostar, the subcutaneous gliomas derived from the GSCs showed a significant reduction in microvessel density after VAE treatment; (c) compared with the control, a significant improvement was observed in the length of the survival of mice with intracranial and subcutaneous gliomas treated with VAE; (d) MRI analysis showed that the tumor volumes of the intracranial gliomas generated by GSCs remarkably decreased after 10 d of VAE treatment compared with the controls. In conclusion, VAE demonstrated oncolytic therapeutic efficacy in animal models of human GSCs and expressed an endostatin-angiostatin fusion gene, which enhanced antitumor efficacy most likely by restricting tumor microvasculature development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiostatins / biosynthesis*
  • Angiostatins / genetics
  • Animals
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / pathology
  • Brain Neoplasms / therapy*
  • Endostatins / biosynthesis*
  • Endostatins / genetics
  • Genetic Therapy
  • Glioblastoma / blood supply
  • Glioblastoma / pathology
  • Glioblastoma / therapy*
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / physiology*
  • Neoplastic Stem Cells / transplantation
  • Neovascularization, Pathologic / therapy
  • Oncolytic Viruses / genetics
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / genetics
  • Simplexvirus / genetics*
  • Tumor Burden
  • Tumor Cells, Cultured

Substances

  • Endostatins
  • Recombinant Fusion Proteins
  • Angiostatins

Grants and funding

This work was supported by a grant from National Natural Science Foundation of China (No. 81071776, 81372354, 81302186), Beijing Natural Science Foundation (No. 7132034) and Beijing Health System High-level Personnel Building Foundation (No. 2013-2-018). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.