Involvement of TNF-alpha in enhancement of invasion and metastasis of colon 26-L5 carcinoma cells in mice by social isolation stress

Psychosocial stress has been implicated in tumor metastasis. We have previo usly reported that social isolation stress exacerbated liver metastasis of colon 26-L5 by partially suppressing the cellular immunity in male Balb/c m ice. To further understand the mechanism underlying the influence of isolat ion stress on liver metastasis, we investigated the effect of social isolat ion stress on tumor invasion, which is considered to be a pivotal step of t umor metastasis. The invasion and migration of tumor cells obtained from tu mor nodules in the isolated mice were more markedly enhanced than that in t he group-housed mice. The mRNA expression of proteolytic proteases, includi ng matrix metalloproteinase (MMP)-2, MMP-9, membrane type 1 (MT1)-MMP, and urokinase-type plasminogen activator (u-PA), were increased in the tumor an d liver tissues of the isolated mice compared with the control mice. On the other hand, production of plasma TNF-alpha and expression of hepatic TNF-a lpha mRNA were elevated in the isolated mice with or without turner burden. Increased TNF-alpha level was particularly discernible in the liver of tum or-bearing mice. Elevated positive staining for TNF-alpha was immunohistoch emically observed within and around tumor mass in the liver from isolated t umor-bearing mice, compared with group-housed mice. In addition, the invasi veness of tumor cells and the expression of proteolytic enzymes, including MMP-9 and u-PA in tumor cells, were enhanced by the treatment of TNF-alpha in vitro. Thus, the data suggested that isolation stress augmented TNF-alph a may be involved in the enhancement of tumor invasion and metastasis in pa rt by upregulating the proteolytic enzymes such as MMPs and u-PA in tumor a nd liver tissues.