Nerve Growth Factor Facilitates the Innervation of Perivascular Nerves in Tumor-Derived Neovasculature in the Mouse Cornea

Abstract

Background: Tumor neovascular vessels are not innervated by perivascular nerves. This study was an investigation of the effects of the nerve growth factor (NGF) on the distribution of perivascular nerves and neovessel formation in tumor tissues. Methods: A gel containing DU145 prostate carcinoma cells or HT1080 fibrosarcoma cells was implanted into mouse corneas. NGF was subcutaneously administered using an osmotic mini-pump. The distribution of perivascular nerves in mouse corneas and densities of CD31-immunopositive neovessels and smooth muscles (α-smooth muscle actin, α-SMA) in tumor tissues were quantified. Summary: Neovessels generated from corneal limber arteries in tumor tissues were observed 4-14 days after the implantation of tumor cells. The density of CD31-immunopositive cells in endothelium increased after the implantation of DU145 or HT1080 cells, while that of α-SMA-immunopositive cells slightly increased. The NGF treatment significantly increased the density of α-SMA- but not that of CD31-immunopositive cells (except for DU145 cells) and resulted in the innervation of perivascular nerves around tumor-derived neovessels, whereas no innervation was observed in the control group. Key Messages: These results suggest that NGF facilitates the innervation of perivascular nerves to regulate blood flow into tumor-derived neovessels.