Growth regulation in animal leukaemia models and in man

Abstract

GROWTH of a population of cells is determined by the size of the growth fraction, the rate of proliferation of that fraction as reflected in cell cycle parameters, and by the rate of cell loss. Cell loss of a compartment is due to cell death and to differentiation. Eventually, differentiation results in an end cell which is incapable of further division and which will eventually die or disappear by other ways. Regulation of growth can take place at all three levels. In normal tissues, cell production matches cell loss under normal physiological conditions. When regeneration occurs following damage, a temporary imbalance in favour of an increase of the population occurs, but the balance is restored shortly after the original size of the population has been attained. Some degree of 'overshoot ' is usually observed, but thereafter equilibrium is rapidly restored. In transplantable solid tumours the proliferating fraction of cells progressively decreases and the percent cell loss increases w~th increasing volume, while the cell cycle parameters remain rather constant [1]. This results in a flattening of the growth curve as the turnout cell population increases its size. A similar pattern of growth may apply to human acute myeloid leukaemia (AML) [2] and is reported for the BNML leukaemic growth in the spleen compartment by Hagenbeek et ak in this Proceedings [3]; following irradiation of a turnout a repopulation occurs during which the fraction of proliferating cells is decreased, but so are the cell cycle time and the cell loss from the tumour [l]. The factors which determine such changes in the 'kinetics' of growing cell populations are largely unknown, but the recognition of certain stimulators of cell proliferation and of chalones has provided some hope of developing means of manipulating turnout cell populations in vivo. Cellular proliferation of certain tumours both in animals and in man, e.g. mammary carcinoma and prostatic carcinoma can be influenced by hormones. Rauscher and Friend type erythroblastosis in mice is promoted by exogenous erythropoietin or by hypoxia and inhibited by hypertransfusion induced polycythemia [445]. The erythroid hyperplasia in Di Guglielmo's syndrome decreases following hypertransfusion [7]. In some cases of chronic myeloid leukaemia (CML), oscillations in the number of peripheral leukaemic cells were observed which suggest the operation of a feedback mechanism [8]. These various observations have suggested that certain cancers and certain leukaemic cells are responsive to physiological regulation mechanisms to a limited extent. Provided this is correct, the logical approach is to identify these mechanisms and subsequently investigate their applicability in bringing the malignant growth under control.