Proliferation of rat liver cells in preneoplastic nodules after stimulation of liver growth by xenobiotic inducers.

Abstract

Several stimulators of adaptive liver growth such as phenobarbital, DDT, and butylhydroxytoluene have been found to promote the development of tumors from preformed carcinogenic lesions in rat liver (Peraino et al., 1975 and 1977). We have found that α-hexachlorocyclohexane (α-HCH), likewise, accelerates the manifestation of malignant liver tumors in rats after initiation of the carcinogenic process by a single dose of diethylnitrosamine (DENA). In order to get more insight into the nature of this promoting effect we studied the influence of α-HCH on cell proliferation in preneoplastic nodules initiated by prior treatment with DENA. 3H-thymidine was injected 1 hour before sacrifice, and auto-radiographs were prepared on histological sections. In the same sections nodules were identified by histochemical demonstration of γ-glutamyltransferase. Labelled cells (= cells involved in DNA synthesis) and mitoses were counted in both nodular and normal tissue. It was found that the rate of proliferation was severalfold higher in the nodules than in the surrounding healthy tissue. Inducers such as α-HCH appear to stimulate the proliferation of nodular cells. From these observations the following conclusions are drawn: (1) Increased rate of proliferation can be used as a diagnostic criterion to identify preneoplastic cells. Control of proliferation in these cells can be studied by the methods used. (2) The findings add support to the current concept that the preneoplastic nodules in the liver are predecessors of malignant cells. (3) The apparent stimulation of nodular cell proliferation by inducers such as α-HCH indicates promoting activity of these compounds and allows separation from initiating activity. Key wordsRat liverPreneoplastic nodulesCell proliferationα-hexachlorocyclohexaneCyproterone acetate