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

Abstract

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.

Modulation of tumor cell susceptibility to cytokine‐induced cell death by hormones, growth factors, and cell density

“…This demonstrates that TC susceptibility to the induction of cell death by SU is increased by agents that stimulate GUS transit and suggests that the dying TC fraction is actually not arrested in GliGO but rather continues to prepare itself for GliS transit and is prevented from entering S phase by induction of the lytic pathway. In aggreement with this view, previous data (Horn et al, 1991) show that the surviving TC fraction is a population that displays decreased expression of the proliferation-associated nuclear antigen Ki67 and thus has entered the quiescent state GO. This G1 to GO transit is caused by growth inhibitory signals generated during MO/TC interaction.…”

“…SU gained from MOiTC inter-action cultures closely mimic the effects exerted by MO on TC during direct interaction (Van der Bosch et al, 1990;Horn et al, 1991). The following characteristics are especially to be mentioned.…”

“…l a : *----*I. It has been demonstrated previously by flow cytometric cell cycle analysis that exposure to MO or SU leads t o accumulation of the entire TC population in G1 within 16 to 24 h ( Van der Bosch et al, 1990;Horn et al, 1991). In the present work cell cycle phase distributions were determined routinely by recording nuclear size distributions, which have been shown to reflect closely cellular DNA content (Butler, 1984).…”

“…According to previous flow cytometric data (Van der Bosch et al, 1990;Horn et al, 1991) and to the nuclear size distribution patterns observed under the influence of SU (Fig. 2), the dying cell population consists of G1 cells.…”

“…We have recently reported on interactions between human monocytes (MO) and several clonal human TC lines in a serum-free in vitro environment (Van der Bosch et al, 1990;Horn et al, 1991). In this system, induction of TC death by MO critically depends on the growth state of the tumor cell population.…”