Stress Influence On Development Of Hepatocellular Tumors In Transgenic Mice Overexpressing Tgfet

Abstract

We investigated whether stress increases tumorigenesis in male transgenic mice that over express the gene encoding human transforming growth factor aæ (TGFæ). At the age of 10–15 months, these mice begin to develop spontaneous hepatocellular carcinomas at high incidence. The male TGFæ mice were housed with their siblings (non-stressful environment), housed in social isolation, or housed with aggressive non-siblings (stressful environment). Some animals in each group were exposed once a week to a second stressor (swim stress), beginning at the age of 7 months. Housing with aggressive non-siblings increased neoplastic growth in the male TGFæ mice: the incidence and multiplicity of liver tumors, and tumor burden were higher in these animals than in the sibling-housed mice. Among the isolated TGFæ mice, only the tumor burden was increased, when compared with the sibling-housed TGFæ mice. Swim stress significantly increased the incidence of liver tumors and tumor burden in the sibling-housed TGFæ mice. Plasma levels of 17β-estradiol (E2) that are elevated in the TGFæ mice, were modestly but significantly higher in the non-sibling housed transgenic mice than in the sibling-housed. Natural killer (NK) cell activity, reduced in these mice, was not affected by housing environment. These data suggest that stress promotes the growth of hepatocellular tumors in the male TGFæ mice. Whether estrogens are involved in mediating this association remains to be determined.