The malignant transformation as a metabolic steady state transition: The possible significance of the phasing of enzyme synthesis and related aspects

It has been suggested by Sel'kov and by the author that the malignant transformation may be due to a transition between alternative steady states at the metabolic level without necessarily involving a genetic defect. It had previously been indicated by the author that the properties of a cell can be expected to reflect its pattern of temporal organisation. These two aspects are now considered in relation to one another by examining the behaviour of a coupled enzymic system (involving substrate inhibition characteristics) which is capable of exhibiting multiple steady states. It is shown that the phasing of the synthesis of the enzymes concerned during the cell cycle (normal or disturbed as a result of the action of agents) can determine whether a transition occurs or not and also if it is stable or not. It is also pointed out that the phasing between the fluctuations in the levels of inhibitors and activators of the enzymes involved and in their isozyme patterns can be equally significant in these respects. Hence a transition can be effected by a variety of agents acting at diverse sites within or without the cell. The transition is discussed as an example of a process that may be involved in the malignant transformation. It is emphasized that once a transition has occurred in a cell, there is no reason to presuppose that the new state cannot be inherited by the progeny of that cell, despite the removal of the causative agent: reversal is possible, however, and is discussed as an explanation for abortive oncogenic transformation. Other aspects briefly discussed in relation to metabolic steady state transitions include - the random nature and distribution of transformation in culture; the heterogeneity of transformed cells; resistance to transformation; the significance of the timing and duration of action of an oncogenic agent; the effect of gene duplication on the ‘fixation’ of the transformation; cell death. Finally it is pointed out that the same considerations are likely to apply to other systems exhibiting multiple steady states as a result of the existence of the phenomenon of hysteresis and hence probably to genetic switch systems also.