Suppression of tumor cell susceptibility to monocyte-induced cell death by growth-inhibitory signals generated during monocyte/tumor cell interaction.

In a recently established serum-free in vitro system it has been demonstrated that the susceptibility of various human tumor cells to the induction of cell death by elutriated human monocytes is critically dependent on tumor cell density and growth state. In the present work it is shown by flow cytofluorometric analysis of bromodeoxyuridine incorporation rates and of expression of the proliferation-associated nuclear antigen Ki-67, that tumor cells forced out of the cell cycle into the quiescent state (G0), which can be accomplished by treatment with supernatant from monocyte/tumor cell interaction cultures, are no longer susceptible to the induction of cell death by monocytes. This suggests that processes essential for the lytic pathway cannot take place in quiescent cells. It is furthermore demonstrated that tumor cells are driven into G0 during interaction with monocytes and that the rate of transit from G1 to G0 increases with increasing monocyte dosage. This explains our earlier finding that maximum rates of tumor cell death are induced at rather low monocyte:tumor cell ratios of around 1:2 and that lysis is suppressed at higher monocyte dosages (van der Bosch et al.:Exp Cell Res 187:185-192, 1990). The potential significance of these findings for the supposed function of mononuclear phagocytes in tumor defense lies in the notion that tumor cells driven into G0 might escape this control and that signals involved in monocyte/tumor cell-interaction contribute to the accumulation of tumor cells in G0.