Counteracting effects of dexamethasone and α2-macroglobulin on inhibition of proliferation of normal and neoplastic rat hepatocytes by transforming growth factors-β type 1 and type 2

✍ Scribed by G. K. Wollenberg; J. Lamarre; E. Semple; E. Farber; J. Gauldie; M. A. Hayes

• Publisher: John Wiley and Sons
• Year: 1991
• Tongue: French
• Weight: 699 KB
• Volume: 47
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910470223

✦ Synopsis

Primary cultures of hepatocytes isolated from normal F-344 rats or from F-344 rats with hepatocellular carcinomas generated by a 2-step model of chemical carcinogenesis were used to determine if dexamethasone (DEX) or a,-macroglobulin (a,M) modify the ability of transforming growth factors-p type I (TGF-PI) and type 2 (TGF-p2) to inhibit labelling index of hepatocytes cultured continuously with or without epidermal growth factor (EGF). Both TGF-PI and p2 were equivalently potent inhibitors of S-phase DNA synthesis in normal and neoplastic hepatocytes as determined by 'H-thymidine autoradiography. Both DEX (1 to 100 PM) and a,M (SCrZOO PM) partially counteracted the mito-inhibitory effect of both TGF-Ps on the proliferation of normal and surrounding hepatocytes. In contrast, neoplastic hepatocytes cultured with DEX released much less immunoreactive a,M and were less able to overcome the inhibitory effect of TGF-f3 than normal or surrounding hepatocytes. Purified bovine a,M partially counteracted the inhibition of TGF-p I or P2 of both surrounding and neoplastic hepatocytes. Both DEX and a,M were more effective against the mito-inhibitory activity of TGF-P2. Our data suggest that a,M released by DEX-treated normal hepatocytes contributes to the counteraction of the TGF-f3 effect by DEX. Our results support the hypothesis that glucocorticoids and growth-factor-binding proteins may have important roles in modulating the effects of TGF-p on normal hepatocyte proliferation and suggest that under some conditions hepatocellular neoplasms can be more sensitive than normal hepatocytes to inhibition of proliferation by TGF-P.