Density-dependent growth of normal and nodular hepatocytes

To elucidate factors responsible for altered proliferation of preneoplastic hepatocytes in rat hepatocarcinogenesis in vivo, EGF-stimulated DNA synthesis of normal and nodular hepatocytes in primary culture was studied. In addition, the influence of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated to clarify whether this potent tumor promoter differentially affects normal and nodular hepatocyte cultures. Unexpectedly it was found that in nodular hepatocytes spontaneous and EGF-stimulated DNA synthesis was enhanced with increasing cell density while DNA synthesis was inhibited in dense cultures of normal hepatocytes. Mitogenic responses were detected both by [3H]thymidine incorporation into DNA and by 5-bromo-2'-deoxyuridine labeling indices. TCDD (1 nM) acted as a mitoinhibitor both in normal and in nodular hepatocytes. The results suggest marked differences in growth behavior of nodular versus normal hepatocyte cultures probably due to paracrine stimulation by growth factors and altered cell-cell interaction.