Density-dependent limitation of growth and the regulation of cell replication by changes in the triggering level of the cell cycle switch

Abstract

If the initiation/suppression of cell replication results from the operation of an intracellular switch, then proliferation control can be expected to occur through the modulation of its threshold setting or sensitivity. Assuming the existence of a threshold and the uptake of regulators by an equilibrium process, one can explain various types of dependency of the maximum cell density on the initial level of the regulator (e.g., serum) in the medium. Moreover it becomes theoretically possible to distinguish whether an altered threshold or equilibrium constant is responsible for modified proliferation characteristics. It is pointed out that some published data on transformed cells are more consistent with an altered threshold than the permeability change invoked. Other data suggests that transformation has produced more complex effects. The arguments presented indicate that while some cells may be more susceptible to control via changes in the relevant equilibrium constant, others may respond more markedly to threshold modulation. If control occurs through inhibition of replication, it is possible for the system to exhibit a critical “mass”: if this is exceeded (in ways discussed) proliferation could continue indefinitely provided adequate nutrients are available. An oscillator concept of the cell cycle accounts for the existence of a threshold and also permits a general understanding of its modulation by multiple agents. It is concluded that at least some forms of cancer are the result of altered thresholds.