The circadian control of cell Proliferation and Differentiation has been studied principally in rat liver. The comparison between the differentiation by hepatic enzymes and the division by the cell cycle under various experimental conditions (postnatal maturation, regeneration after partial hepatectomy, adrenalectomy, corticosterone treatments etc.) leads to the following conclusions: Under physiological conditions, proliferation and differentiation activities present a mutually exclusive relationship with a specific circadian rhythm. For both functions, the circadian variation of corticosterone plays the role of synchronizer, each evening (peak) it induces the synthesis of tissue specific enzymes in G0 cells and simultaneously inhibits the DNA synthesis in cycling cells. The same parameters have been studied during the different stages of hepatocarcinogenesis induced by Diethylnitrosamine (DEN). After initiation alone, (DEN for 2 weeks) circadian control is unchanged and precancerous cells are not able to reach malignancy. Promotion (DEN for 6 weeks) consists of disturbing the circadian synchronization to liberate the selective growth of initiated precancerous cells. This proliferation advantage favours the accumulation of chromosomal aberrations including those implicated in malignant transformation: i.e. activation of oncogenes or inhibition of antioncogenes.

Animals↗

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The role of corticoids, adrenalectomy, phenobarbital and pentobarbital in the promotion of DEN-hepatocarcinogenesis.

This paper shows there is a good correlation between the disturbance of the proliferation control and the plasma Corticosterone circadian pattern on the one hand and the promotion of diethylnitrosamine (DEN) initiated precancerous lesions on the other. In normal rats, phenobarbital (PB) or adrenalectomy, which both decrease plasma corticosterone levels, induce chronic liver growth, enhance the mitotic response to partial Hepatectomy and eliminate the mitotic circadian rhythms. In rats treated by DEN, the same treatments increase the proliferation advantage of PAS positive precancerous cells and promote tumorogenesis. Daily corticosterone injections inhibits liver growth even after hepatectomy both in normal and DEN-treated rats. Under carcinogenic conditions (DEN for 6 weeks), corticoid injections inhibit the selective growth of precancerous cells and the death by cancer occurs later. Pentobarbital (PE), administrated at the same subsedative doses as PB, does not change plasma corticosterone levels nor the mitotic control and does not enhance the carcinogenesis initiated by DEN. The "promoting effect" is closely linked to the disturbance of the biological corticosterone activity that normally synchronizes the liver cell proliferation by temporary inhibition of DNA synthesis for some hours every day (14-16). The role played by corticosterone in the selective growth of precancerous foci (glycogenesis type I) is discussed in the light of the hypothesis (1-2) according to which modification of the carbohydrate metabolism is closely related to the process of hepatocarcinogenesis.

Adrenalectomy↗