Nerve growth factor (NGF) has an anti-tumor effects through perivascular innervation of neovessels in HT1080 fibrosarcoma and HepG2 hepatitis tumor in nude mice

Abstract

This study investigated whether NGF prevents tumor growth by promoting neuronal regulation of tumor blood flow. HT1080 fibrosarcoma cells or HepG2 hepatitis cells were subcutaneously implanted into nude mice. On Day 21 after the implantation of tumor cells, human NGF (40 or 80 ng/h for 14 days) was administered using a micro-osmotic pump. Growth rates of both tumors were significantly inhibited by the treatment of NGF, and the survival rate was also extended. Significant suppression of HT1080 tumor growth lasted after withdrawing NGF. NGF markedly increased the density of α-smooth muscle actin (α-SMA)-immunoreactive (ir) cells without changing neovessel density in HT1080 tumor tissues. Double immunostaining demonstrated protein gene product (PGP) 9.5-ir nerves around α-SMA-ir cells were found in HT1080 tumor tissue treated with NGF. The blood flow in HepG2 tumors treated with saline was significantly higher than in the non-tumor control area, but the tumor blood flow was markedly reduced by NGF treatment. In in vitro studies, NGF significantly accelerated migration of aortic smooth muscle cells but not endothelial cells, whereas NGF had no cytotoxic action on both cells. NGF inhibits tumor growth via indirect action, probably through innervation and maturation of tumor neovasculature, which regulates blood flow into tumor tissues.