Liver cell control after discontinuation of DENA feeding in hepatocarcinogenesis

Abstract

The mitotic response following a partial hepatectomy, the nyctohemeral rhythm of these mitoses and the ‘chalone activity’ measured by the inhibitory effect of liver extracts on the normal liver regeneration have been studied in order to estimate the evolution of mitotic control in the liver of rats treated by DENA for 2, 4, 6 and 10 weeks. These parameters and the pathological lesions (preneoplastic foci, neoplastic nodules and hepatomas) have been followed up after stopping the DENA feeding. A good correlation has been found between the malignant transformation of preneoplastic foci and the breakdown of the mitotic control. In animals treated by DENA for two weeks, the homeostatic control of mitoses remains normal for a minimum of 14 months and ‘preneoplastic foci’ persist without any further malignant transformation. After DENA feeding for 4 and 6 weeks, the subsequent malignant transformation occurs as a function of the mitotic disturbance: the longer the DENA feeding, the faster the homeostatic disturbance, the earlier the conceration. After DENA treatment for 10 weeks, the homeostatic regulation is lost and the neoplastic growth is triggered at the time of the DENA feeding cessation. In this case, the pattern of canceration is the same as when DENA is given continuously up to the time of death. It is concluded that ‘preneoplastic foci’ induced during the first two weeks of treatment cannot by themselves transform into a malignant tumor. To commit them irreversibly into malignancy, a subsequent action of the carcinogen is necessary; it may consist of the irreversible breakdown of the normal homostatic regulatory mechanism of liver cell proliferation.