Caspase-8 is frequently deficient in several kinds of human
tumors, suggesting that certain effects of this
enzyme restrict
tumor development. To examine the nature of the cellular function whose regulation by
caspase-8 contributes to its antitumor effect, we assessed the impact of
caspase-8 deficiency on cell transformation in vitro. Caspase-8-deficient mouse embryonic fibroblasts immortalized with the SV40
T antigen did not survive when cultured in soft
agar, and were nontumorogenic in nude mice. However, the rate of transformation of these cells during their continuous growth in culture, as reflected in the observed emergence of cells that do grow in soft
agar and are able to form
tumors in nude mice, was far higher than that of cells expressing
caspase-8. These findings indicate that
caspase-8 deficiency can contribute to
cancer development in a way that does not depend on the
enzyme's participation in killing of the
tumor cells by host immune cytotoxic mechanisms, or on its involvement in the cell-death process triggered upon detachment of the cells from their substrate, but rather concerns cell-autonomous mechanisms that affect the rate of cell transformation.