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

Oncol Res. 1999;11(10):461-9.


Psychosocial stress has been implicated in tumor metastasis. We have previously reported that social isolation stress exacerbated liver metastasis of colon 26-L5 by partially suppressing the cellular immunity in male Balb/c mice. To further understand the mechanism underlying the influence of isolation stress on liver metastasis, we investigated the effect of social isolation stress on tumor invasion, which is considered to be a pivotal step of tumor metastasis. The invasion and migration of tumor cells obtained from tumor nodules in the isolated mice were more markedly enhanced than that in the group-housed mice. The mRNA expression of proteolytic proteases, including matrix metalloproteinase (MMP)-2, MMP-9, membrane type 1 (MTI)-MMP, and urokinase-type plasminogen activator (u-PA), were increased in the tumor and 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-alpha mRNA were elevated in the isolated mice with or without tumor burden. Increased TNF-alpha level was particularly discernible in the liver of tumor-bearing mice. Elevated positive staining for TNF-alpha was immunohistochemically observed within and around tumor mass in the liver from isolated tumor-bearing mice, compared with group-housed mice. In addition, the invasiveness 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-alpha may be involved in the enhancement of tumor invasion and metastasis in part by upregulating the proteolytic enzymes such as MMPs and u-PA in tumor and liver tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Immunohistochemistry
  • Liver / metabolism
  • Liver Neoplasms / metabolism*
  • Male
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Social Isolation*
  • Stress, Psychological*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism*
  • Urokinase-Type Plasminogen Activator / metabolism


  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Urokinase-Type Plasminogen Activator
  • Matrix Metalloproteinases