In vitro selection of a cell line for resistance to lysis by tumor necrosis factor-alpha selects for reduced tumorigenicity

Experimentally, TNF-alpha can mediate the hemorrhagic necrosis of certain tumors. Furthermore, evidence indicates that natural cytotoxic (NC) activity, a cell-mediated cytolytic activity that utilizes TNF-alpha in the lysis of target cells, is involved in preventing the outgrowth of certain NC/TNF-alpha-sensitive tumor cells. These observations raise the issue of whether soluble TNF-alpha normally serves as a tumor surveillance mechanism preventing the outgrowth of some tumors. To address this issue, we have used TNF-alpha to select TNF-alpha-resistant variants from the NC/TNF-alpha-sensitive mouse fibroblast cell line 10ME. Previously, we have demonstrated that 10ME is tumorigenic in immune-deficient mice but fails to form tumors in normal mice. Moreover, selection of NC-resistant variants from 10ME selects for both TNF-alpha resistance and tumorigenicity in normal mice. As cells that have been selected for NC resistance form tumors in normal mice, whereas the NC-sensitive parental cell line does not, it seems that escape from NC activity is sufficient to significantly increase the tumorigenic potential of the cell line. We show that the selection with TNF-alpha, although associated with NC resistance, does not increase the tumorigenic potential of 10ME cells but reduces it. Thus, NC activity appears to function as a mechanism to prevent tumor formation, and escape from NC activity allows for tumor formation; TNF-alpha does not have similar activity. Moreover, this suggests that NC activity is not equivalent to soluble TNF-alpha activity, but utilizes TNF-alpha more efficiently than soluble TNF-alpha, or NC activity involves both TNF-alpha and other effector mechanisms.