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Carcinogenesis, Vol. 22, No. 8, 1247-1256, August 2001
© 2001 Oxford University Press

CARCINOGENESIS

Role of transforming growth factor {alpha} and prostaglandins in preferential growth of preneoplastic rat hepatocytes

Karin Hufnagl, Wolfram Parzefall, Brigitte Marian, Monika Käfer, Krystyna Bukowska, Rolf Schulte-Hermann and Bettina Grasl-Kraupp,1

Institut für Krebsforschung, University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria

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. PGE2 or PGF2{alpha} increased expression of TGF{alpha} and DNA replication in GSTp– cells but not in GSTp+ cells. PGA2 and PGJ2 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+ cells; this inhibition was reversed by PGE2/F2{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 PGA2/J2. (iii) SC236, a Cox-2 inhibitor, may have preventive value in hepatocarcinogenesis.


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