Dissociation of two actions in the positíve effect of prior partial hepatectomy on the induction of the hepatocarcinogenic process by diethylnitrosamine

Abstract

Abstract The present study was aimed at re-evaluating the mechanism by which partial hepatectomy (PH) and the resulting mitogenic stimulation act to positively modulate the action of a chemical hepatocarcinogen applied 24 hours after surgery. Using as a marker the immunocytochemical expression of glutathione S-transferase placental form (GST-P), we compared the early incidence of single altered hepatocytes and the time-course of appearance and growth of subsequently developed liver neoplasia in diethylnitrosamine (DENA) treated sham-operated or partially hepatectomized animals. The data showed that, compared to sham-operation, partial hepatectomy increases the frequency of early GST-P positive single hepatocytes appearing 72 h after treatment with DENA (50 mg/kg b.w.), indicating a positive (co-carcinogenic) effect of PH on the frequency of the initiation event. At 2 months after this treatment, foci of altered hepatocytes were about 5 times more numerous in PH-pretreated than in sham-operated animals and their average volume about four times greater. The latter difference persisted for up to 10 months after carcinogen treatment, indicating that the lesions had grown at similar rates in the meantime. The simplest hypothesis to account for this difference in size of the lesions is that it is due to the 2-3 waves of normal-like cell division the altered hepatocytes underwent during the very first days after removal of part of the liver mass, rather than to true promotion or to an intrinsic difference in proliferative phenotype of the initiated cells. The increased size and higher frequency of the lesions in PH-pretreated rats concur to increase the population of cells at risk towards subsequent events implied in multistep progression and, by this, to positively modulate the latter. Accordingly, only PH treated rats had developed neoplastic nodules at 10 months and tumours at 15 months. This can therefore be explained without resorting to the currently held view that cell divisions in PH would increase the carcinogenic efficiency of DENA, due to the fact that resulting cell divisions would intervene before full repair of DENA-induced DNA damages.