Carcinogenesis, Vol 18, 1381-1387, Copyright © 1997 by Oxford University Press
WK Kaufmann, LL Byrd, D Palmieri, RW Nims and JM Rice
A series of promoting and non-promoting barbiturates and hydantoins were
examined for their ability to sustain the growth of a phenobarbital
(PB)-dependent hepatocyte line in cell culture. The effective liver tumor
promoters, pentobarbital, allobarbital and 5- ethyl-5-phenylhydantoin,
replaced PB and supported 6/27C1 hepatocyte colony formation in vitro at
52-87% of the level induced by PB. The weak promoters secobarbital and
amobarbital supported colony formation at only 11-19% of the PB control. A
significant correlation was observed for in vivo and in vitro promotion
activities of barbiturates and hydantoins, indicating that clonal expansion
by 6/27C1 hepatocytes was promoter-dependent. Cell density also appeared to
influence hepatocyte growth in vitro. Hepatocyte colonies acquired the
ability to grow in the absence of PB, such that after 10 days incubation
with PB, approximately 50% of colonies continued to grow in the absence of
promoter. This phenomenon of clone-size-dependent hepatocyte growth
suggested the operation of an autocrine growth factor pathway. Addition of
the hepatocyte mitogen and autocrine growth factor, transforming growth
factor-alpha (TGF-alpha), to culture medium lacking PB induced a
dose-dependent increase in 6/27C1 hepatocyte colony formation. At the
optimal concentration of 3 ng/ml, TGF-alpha sustained hepatocyte clonal
expansion at 84% of the level induced by 2 mM PB. Individual 6/27C1
colonies that grew from single cells in the presence of TGF-alpha were
tested for promoter-dependent colony formation. Either PB or TGF-alpha
supported colony formation by these cells at similar levels and when
combined at optimal concentrations, the response appeared to be saturated.
When these factors were tested in combination at suboptimal concentrations,
the two compounds were additive for supporting colony formation by the
parental 6/27C1 line. The ability of TGF-alpha to replace PB and sustain
hepatocyte clonal expansion was confirmed with the tumorigenic 6/15
hepatocyte line. These results suggest that TGF- alpha and PB may promote
hepatocarcinogenesis by stimulating a common signal transduction pathway.
ARTICLES
TGF-alpha sustains clonal expansion by promoter-dependent, chemically initiated rat hepatocytes
Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599-7295, USA.
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