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Counteracting effects of dexamethasone and α 2 ‐macroglobulin on inhibition of proliferation of normal and neoplastic rat hepatocytes by transforming growth factors‐β type 1 and type 2
Author(s) -
Wollenberg G. K.,
Lamarre J.,
Semple E.,
Farber E.,
Gauldie J.,
Hayes M. A.
Publication year - 1991
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910470223
Subject(s) - hepatocyte , transforming growth factor , epidermal growth factor , endocrinology , dna synthesis , medicine , biology , tgf alpha , growth factor , dexamethasone , cell growth , neoplastic cell , carcinogenesis , growth inhibition , cell culture , receptor , in vitro , cell , biochemistry , cancer , genetics
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 α 2 ‐macroglob‐ulin (α 2 M) modify the ability of transforming growth factors‐β type 1 (TGF‐β1) and type 2 (TGF‐β2) to inhibit labelling index of hepatocytes cultured continuously with or without epidermal growth factor (EGF). Both TGF‐β1 and β2 were equivalently potent inhibitors of S‐phase DNA synthesis in normal and neoplastic hepatocytes as determined by 3 H‐thymidine autoradiography. Both DEX (1 to 100 μM) and α 2 M (50‐200 μm) partially counteracted the mito‐inhibitory effect of both TGF‐βs on the proliferation of normal and surrounding hepatocytes. In contrast, neoplastic hepatocytes cultured with DEX released much less immunoreactive α 2 M and were less able to overcome the inhibitory effect of TGF‐β than normal or surrounding hepatocytes. Purified bovine α 2 M partially counteracted the inhibition of TGF‐β1 or β2 of both surrounding and neoplastic hepatocytes. Both DEX and α 2 M were more effective against the mito‐inhibitory activity of TGF‐β2. Our data suggest that α 2 M released by DEX‐treated normal hepatocytes contributes to the counteraction of the TGF‐β 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‐β 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‐β.