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 synthe sis of normal and nodular hepatocytes in primary culture was studied. In ad dition, the influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was inv estigated to clarify whether this potent tumor promoter differentially affe cts normal and nodular hepatocyte cultures. Unexpectedly it was found that in nodular hepatocytes spontaneous and EGF-stimulated DNA synthesis was enh anced with increasing cell density while DNA synthesis was inhibited in den se cultures of normal hepatocytes. Mitogenic responses were detected both b y [H-3]thymidine incorporation into DNA and by 5-bromo-2'-deoxyuridine labe ling indices. TCDD (1 nM) acted as a mitoinhibitor both in normal and in no dular hepatocytes. The results suggest marked differences in growth behavio r of nodular versus normal hepatocyte cultures probably due to paracrine st imulation by growth factors and altered cell-cell interaction. (C) 2000 Els evier Science Ireland Ltd. All rights reserved.