We have previously shown that
tumor necrosis factor-alpha (
TNF-alpha), which is an important angiogenesis-related factor, was over-secreted in male BALB/c mice under social isolation stress as compared with the control, and closely associated with a remarkable elevation of
tumor invasion and
metastasis of colon 26-L5
carcinoma cells. In the present study, we explored the effect of isolation stress on the angiogenesis caused by colon 26-L5
carcinoma cells in vivo and in vitro. Social isolation lead to the enhancement of
tumor growth after intrahepatic implantation with a fragment of colon 26-L5
tumor. Angiogenic response (number of vessels oriented towards
tumor mass) and
tumor growth (size) were significantly increased in the socially isolated mouse relative to that in the group-housed mice. Furthermore, higher
protein level of hepatic
TNF-alpha was found in the stressed mice than that in the control. Expression of
mRNA for
vascular endothelial growth factor (
VEGF) and
hepatocyte growth factor (HGF) were also elevated in the
tumor regions and liver tissues of the stressed mice in comparison with that in group-housed mice. On the other hand, hepatic sinusoidal endothelial (HSE) cells treated with
TNF-alpha exhibited a marked promotion of the migration, invasion, expression of
mRNA for
matrix metalloproteinase (MMP)-9, and tube-like formation, but no cytotoxicity against the cells in vitro. The above data suggest that the social isolation stress augmented the
tumor-induced angiogenesis probably by up-regulating the angiogenesis-related factors, including
TNF-alpha,
VEGF and HGF, and consequently mediating the functions of endothelial cells such as migration, invasion, and tube-like formation.