Social isolation stress augments angiogenesis induced by colon 26-L5 carcinoma cells in mice

We have previously shown that tumor necrosis factor-alpha (TNF-alpha), whic h is an important angiogenesis-related factor, was over-secreted in male BA LB/c mice under social isolation stress as compared with the control, and c losely associated with a remarkable elevation of tumor invasion and metasta sis of colon 26-L5 carcinoma cells. In the present study, we explored the e ffect of isolation stress on the angiogenesis caused by colon 26-L5 carcino ma 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 isola ted mouse relative to that in the group-housed mice. Furthermore, higher pr otein level of hepatic TNF-alpha was found in the stressed mice than that i n the control. Expression of mRNA for vascular endothelial growth factor (V EGF) and hepatocyte growth factor (HGF) were also elevated in the tumor reg ions and liver tissues of the stressed mice in comparison with that in grou p-housed mice. On the other hand, hepatic sinusoidal endothelial (HSE) cell s treated with TNF-alpha exhibited a marked promotion of the migration, inv asion, expression of mRNA for matrix metalloproteinase (MMP)-9, and tube-li ke formation, but no cytotoxicity against the cells in vitro. The above dat a suggest that the social isolation stress augmented the tumor-induced angi ogenesis probably by up-regulating the angiogenesis-related factors, includ ing TNF-alpha, VEGF and HGF, and consequently mediating the functions of en dothelial cells such as migration, invasion, and tube-like formation.