Role of transforming growth factor α and prostaglandins in preferential growth of preneoplastic rat hepatocytes

The role of transforming growth factor alpha (TGF alpha) and prostaglandins (PGs) in the preferential growth of preneoplastic liver cells was studied. Rats received the genotoxic hepatocarcinogen N-nitrosomorpholine (NNM); placental glutathione S-transferase (GSTp) was used as a marker to identify preneoplastic foci. Preneoplastic foci expressing TGF alpha (TGF alpha (+)) grew more rapidly than TGF alpha negative (TGF alpha (-)) ones. Almost all tumours studied were positive for TGF alpha. The key enzymes of prostaglandin synthesis, cyclooxygenase I (Cox-1) and II (Cox-2), were present in all unaltered and preneoplastic cells and tended to decrease in the later stages of hepatocarcinogenesis. Immunostaining revealed that cultures of hepatocytes, isolated from NNM-treated livers by collagenase perfusion, contained 1-2% GSTp-positive (GSTp(+)) and 9% TGF alpha (+) hepatocytes; 0.6% of the cells were GSTp(+)/TGF alpha (+). Cox-1 and Cox-2 were present in all cells. DNA replication was almost exclusively associated with expression of TGF alpha. GSTp(+) hepatocytes showed a 3- to 4-fold higher probability of TGF alpha expression and of DNA synthesis than GSTp-negative (GSTp(-)) cells. PGE(2) or PGF(2 alpha) increased expression of TGF alpha and DNA replication in GSTp- cells but not in GSTp(+) cells. PGA(2) and PGJ(2) decreased DNA synthesis in TGF alpha (+) cells without an obvious effect on the intracellular levels of TGF alpha. The Cox-2 inhibitor SC236 suppressed DNA replication preferentially in GSTp I cells; this inhibition was reversed by PGE(2)/F-2 alpha. Indomethacin had no effect. These results suggest the following conclusions. (i) Growth regulation of preneoplastic GSTp+ cells in culture exhibits distinct differences from GSTp- cells and elevated expression of TGF alpha contributes to their growth advantage. (ii) TGF alpha renders preneoplastic hepatocytes sensitive to suppression of DNA synthesis by PGA(2)/J(2). (iii) SC236, a Cox-2 inhibitor, may have preventive value in hepatocarcinogenesis.