Regulation of selection of liver nodules initiated with N-nitrosodiethylamine and promoted with nodularin injections in Fischer 344 male rats by reciprocal expression of transforming growth factor-beta 1 and its receptors

To investigate how glutathione-s-transferase placental form (GST-P)+ hyperp lastic nodules (HNs) are selected and to determine the driving force for pr ogression or regression of HNs, changes in transforming growth factor-beta 1 (TGF-beta) and its receptors were examined during hepatocarcinogenesis in itiated by N-nitrosodiethylamine (DEN) and promoted by nodularin. The induc tion of TGF-beta 1 expression in the GST-P+ HNs was dependent on nodularin injections for 10 wk, which started the third week after DEN initiation. Th e kinetics of TGF-beta 1 induction during carcinogenesis were quite differe nt from that of simple regeneration after partial hepatectomy (PH): hepatoc ytes initiated with DEN alone induced TGF-beta 1 expression for 24 d, and s ubsequent stimulation by PH on the fourteenth day after DEN initiation supe r-induced TGF-beta 1 mRNA (50 times that of the control level), as opposed to a transient expression for less than 5 d by PH alone. GST-P+ HNs did not express TGF-beta receptors I (RI) and II (RII) during the early stage of c arcinogenesis, whereas the surrounding hepatocytes strongly expressed both of these receptors. On cessation of nodularin injection, however, the expre ssion of RI and RII in the HNs changed significantly: RII+ nodules appeared , and the number and area of RII+/- nodules were significantly increased at 10 wk after the cessation. These findings indicate that induction of TGF-b eta expression in GST-P+ HNs might be a strong selection pressure that allo ws outgrowth of RII- nodules during liver carcinogenesis. (C) 1999 Wiley-Li ss, Inc.