Herpes simplex virus amplicon delivery of a hypoxia-inducible angiogenic inhibitor blocks capillary formation in hepatocellular carcinoma

Richard H. Pin, Maura Reinblatt, William J. Bowers, Howard J. Federoff, Yuman Fong, S. Vickers, M. Callery

Research output: Contribution to journalArticlepeer-review

Abstract

Tumor hypoxia induces vascular endothelial growth factor (VEGF) expression, which stimulates tumor angiogenesis. The VEGF pathway is inhibited by soluble VEGF receptors (soluble fetal liver kinase-1 [sFlk-1]) that bind VEGF and block its interaction with endothelial cells. Herpes simplex virus (HSV)-derived amplicons are replication-incompetent viruses used for gene delivery. We attempt to attenuate angiogenesis and inhibit hepatoma growth through amplicon-mediated expression of sFlk-1 under hypoxic control. A multimerized hypoxia-responsive enhancer (10xHRE) was cloned upstream of the sFlk-1 gene (10xHRE/sFlk-1). An amplicon expressing 10xHRE/sFlk-1 was genetically engineered (HSV10xHRE/sFlk-1). SK-HEP-1 human hepatoma cells were transduced with HSV10xHRE/sFlk-1 and incubated in normoxia (21% O2) or hypoxia (1% O2). Human umbilical vein endothelial cell assay evaluated capillary inhibition. Western blot assessed sFlk-1 expression. SK-HEP-1 flank tumors (n = 24) in athymic mice were treated with HSV10xHRE/sFlk-1. Media from hypoxic SK-HEP-1 transduced with HSV10xHRE/sFlk-1 yielded an 80% reduction in capillary formation (P < 0.005), whereas normoxic SK-HEP-1 yielded a 25% reduction (P < 0.05). Western blot of SK-HEP-1 transduced with HSV10xHRE/sFlk-1 demonstrated greater sFlk-1 expression in hypoxia vs. normoxia. SK-HEP-1 tumors treated with HSV10xHRE/sFlk-1 yielded a 72% reduction in volume vs. the control group (P < 0.000001). HSV amplicon-mediated delivery of a hypoxia-inducible soluble VEGF receptor substantially reduces new vessel formation and tumor growth in hepatoma.

Original languageEnglish (US)
Pages (from-to)812-823
Number of pages12
JournalJournal of Gastrointestinal Surgery
Volume8
Issue number7
DOIs
StatePublished - Jan 1 2004

Keywords

  • Flk-1
  • Gene therapy
  • Herpes simplex virus
  • Hypoxia-inducible factor 1
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

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