Herpes simplex virus amplicon delivery of a hypoxia-inducible soluble vascular endothelial growth factor receptor (sFlk-1) inhibits angiogenesis and tumor growth in pancreatic adenocarcinoma Journal Article
| Authors: | Reinblatt, M.; Pin, R. H.; Bowers, W. J.; Federoff, H. J.; Fong, Y. |
| Article Title: | Herpes simplex virus amplicon delivery of a hypoxia-inducible soluble vascular endothelial growth factor receptor (sFlk-1) inhibits angiogenesis and tumor growth in pancreatic adenocarcinoma |
| Abstract: | Background: Tumor hypoxia induces vascular endothelial growth factor (VEGF) expression, which stimulates angiogenesis and tumor proliferation. The VEGF signaling pathway is inhibited by soluble VEGF receptors (soluble fetal liver kinase 1; sFlk-1), which bind VEGF and block its interaction with endothelial cells. Herpes simplex virus (HSV) amplicons are replication-incompetent viruses used for gene delivery. We attempted to attenuate angiogenesis and inhibit pancreatic tumor growth through HSV amplicon-mediated expression of sFlk-1 under hypoxic control. Methods: A multimerized hypoxia-responsive enhancer (10 x HRE) was cloned upstream of the sFlk-1 gene (10 x HRE/sFlk-1). A novel HSV amplicon expressing 10 x HRE/sFlk-1 was genetically engineered (HSV10 x HRE/sFlk-1).Human pancreatic adenocarcinoma cells (AsPC1) were transduced with HSV10 x HRE/sFlk-1 and incubated in normoxia (21% oxygen) or hypoxia (1% oxygen). Capillary inhibition was evaluated by human umbilical vein endothelial cell assay. Western blot assessed sFlk-1 expression. AsPC1 flank tumor xenografts (n = 24) were transduced with HSV10 x HRE/sFlk-1. Results: Media from normoxic AsPC1 transduced with HSV10 x HRE/sFlk-1 yielded a 36% reduction in capillary formation versus controls (P < .05), whereas hypoxic AsPC1 yielded a 76% reduction (P < .005). Western blot of AsPC1 transduced with HSV10 x HRE/sFlk-1 demonstrated greater sFlk-1 expression in hypoxia versus normoxia. AsPC1 flank tumors treated with HSV10 x HRE/sFlk-1 exhibited a 59% reduction in volume versus controls (P < .000001). Conclusions: HSV amplicon delivery of a hypoxia-inducible soluble VEGF receptor significantly reduces new vessel formation and tumor growth. Tumor hypoxia can thus be used to direct antiangiogenic therapy to pancreatic adenocarcinoma. © 2005 The Society of Surgical Oncology, Inc. |
| Keywords: | controlled study; human cell; angiogenesis inhibitor; nonhuman; pancreatic neoplasms; adenocarcinoma; mouse; gene expression; tumor volume; animal experiment; animal model; tumor xenograft; cell assay; vasculotropin receptor 2; angiogenesis; vascular endothelial growth factor receptor-2; genetic transduction; genetic vectors; hypoxia; molecular cloning; blotting, western; genetic engineering; cancer cell; amplicon; western blotting; vascular endothelial growth factor; simplexvirus; pancreas adenocarcinoma; cell hypoxia; pancreatic cancer; tumor growth; neovascularization, physiologic; angiogenesis inhibitors; herpes simplex virus; virus vector; hypoxia-inducible factor 1; incubation time; viral gene therapy; enhancer elements (genetics); flk-1 |
| Journal Title: | Annals of Surgical Oncology |
| Volume: | 12 |
| Issue: | 12 |
| ISSN: | 1068-9265 |
| Publisher: | Springer |
| Date Published: | 2005-12-01 |
| Start Page: | 1025 |
| End Page: | 1036 |
| Language: | English |
| DOI: | 10.1245/aso.2005.03.081 |
| PUBMED: | 16244806 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 14" - "Export Date: 24 October 2012" - "CODEN: ASONF" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work