Multimutated Herpes Simplex Virus G207 Is a Potent Inhibitor of Angiogenesis

Abstract

The mode of the antitumoral activity of multimutated oncolytic herpes simplex virus type 1 G207 has not been fully elucidated yet. Because the antitumoral activity of many drugs involves the inhibition of tumor blood vessel formation, we determined if G207 had an influence on angiogenesis. Monolayers of human umbilical vein endothelial cells and human dermal microvascular endothelial cells, but not human dermal fibroblasts, bronchial epithelial cells, and retinal glial cells, were highly sensitive to the replicative and cytotoxic effects of G207. Moreover, G207 infection caused the destruction of endothelial cell tubes in vitro. In the in vivo Matrigel plug assay in mice, G207 suppressed the formation of perfused vessels. Intratumoral treatment of established human rhabdomyosarcoma xenografts with G207 led to the destruction of tumor vessels and tumor regression. Ultrastructural investigations revealed the presence of viral particles in both tumor and endothelial cells of G207-treated xenografts, but not in adjacent normal tissues. These findings show that G207 may suppress tumor growth, in part, due to inhibition of angiogenesis.

Dominant-Negative Fibroblast Growth Factor Receptor Expression Enhances Antitumoral Potency of Oncolytic Herpes Simplex Virus in Neural Tumors

“…Furthermore, as the FGF signaling pathway is critical to tumor growth and angiogenesis, the enhanced potency should be seen in both FGF-secreting and FGF-nonsecreting tumors, thus broadening the application of the vector. Of note, our data support previous publications that oncolytic HSV mutants with deletions in c34.5 and/or ICP6 have antiangiogenic activities by themselves, inhibiting capillary tube formation in vitro and in vivo and replicating in tumor endothelial cells but not in normal vasculature in vivo (41,42). We showed that G47D is a potent antiangiogenic virus; it significantly reduced endothelial cell proliferation by direct cell killing as well as HUVEC migration in a Transwell coculture system, presumably due to a reduction in angiogenic factors secreted by infected tumor cells.…”

Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment

“…11,45,46 In one study, mice bearing rhabdomyosarcoma xenografts were injected intratumorally with G207. 45 Eight days post injection, endothelial structures were found to be absent in the vector-injected lesions, and the authors detected enveloped viral particles in endothelialcell cytoplasms. 45 Other studies showed that G207 enhanced mean blood vessel densities, a finding explained by reduction of the intratumoral levels of the angiogenesis inhibitors thrombospondin-1 and 2.…”

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

“…Preclinical data regarding herpetic stromal keratitis has revealed enhanced angiogenesis upon infection with wild-type HSV. 25 The situation is more complicated for oncolytic viruses: some well-designed studies indicate that such viruses may have antiangiogenic properties, 24,26 whereas other researchers have reported enhanced angiogenesis occurring via a range of mechanisms. [27][28][29] There are many attempts to engineer viruses to express antiangiogenic molecules.…”