title: Role of transforming growth factor alpha and prostaglandins in preferential growth of preneoplastic rat hepatocytes.
abstract: The role of transforming growth factor alpha (TGFalpha) 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 TGFalpha (TGFalpha(+)) grew more rapidly than TGFalpha negative (TGFalpha(-)) ones. Almost all tumours studied were positive for TGFalpha. 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% TGFalpha(+) hepatocytes; 0.6% of the cells were GSTp(+)/TGFalpha(+). Cox-1 and Cox-2 were present in all cells. DNA replication was almost exclusively associated with expression of TGFalpha. GSTp(+) hepatocytes showed a 3- to 4-fold higher probability of TGFalpha expression and of DNA synthesis than GSTp-negative (GSTp(-)) cells. PGE(2) or PGF(2alpha) increased expression of TGFalpha and DNA replication in GSTp(-) cells but not in GSTp(+) cells. PGA(2) and PGJ(2) decreased DNA synthesis in TGFalpha(+) cells without an obvious effect on the intracellular levels of TGFalpha. The Cox-2 inhibitor SC236 suppressed DNA replication preferentially in GSTp(+) cells; this inhibition was reversed by PGE(2)/F(2alpha). 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 TGFalpha contributes to their growth advantage. (ii) TGFalpha 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.
authors.affiliation: Institut für Krebsforschung, University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Hufnagl
authors.forename: W
authors.initials: W
authors.lastname: Parzefall
authors.forename: B
authors.initials: B
authors.lastname: Marian
authors.forename: M
authors.initials: M
authors.lastname: Käfer
authors.forename: K
authors.initials: K
authors.lastname: Bukowska
authors.forename: R
authors.initials: R
authors.lastname: Schulte-Hermann
authors.forename: B
authors.initials: B
authors.lastname: Grasl-Kraupp
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008297:Male; D011230:Precancerous Conditions / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D016211:Transforming Growth Factor alpha / Q000502:physiology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D016211:Transforming Growth Factor alpha; D005982:Glutathione Transferase