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TRANSFORMING GROWTH FACTOR‐α EXPRESSION IS ALTERED DURING EXPERIMENTAL HEPATOCARCINOGENESIS
Author(s) -
BURR ANDREW W.,
TOOLE KIERAN,
MATHEW JOSEPH,
HINES JULIE E.,
CHAPMAN CLAIRE,
BURT ALASTAIR D.
Publication year - 1996
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/(sici)1096-9896(199607)179:3<276::aid-path573>3.0.co;2-u
Subject(s) - immunohistochemistry , dysplasia , transforming growth factor , hepatocyte , pathology , epidermal growth factor receptor , biology , medicine , epidermal growth factor , endocrinology , receptor , in vitro , biochemistry
In order to characterize the role of transforming growth factor‐α (TGFα) during hepatocarcinogenesis, liver tissue was examined at 10, 16, and 19 weeks following initial 10‐week diethylnitrosamine (50 mg l −1 drinking water) exposure in female Wistar rats. Liver tissue protein extracts were electrophoresed and transferred to nitrocellulose filters. Levels of tissue‐derived TGFα and epidermal growth factor receptor (EGFr) were assessed using an anti‐TGFα monoclonal antibody (Ab‐1) and an anti‐EGFr polyclonal antibody (AB‐4), coupled with scanning densitometric quantification. Immunolocalization of TGFα was performed in Bouin's‐fixed, paraffin‐embedded liver tissue sections. The distribution and intensity of TGFα immunoreactivity varied according to the degree of dysplasia, severely dysplastic cells being strongly immunoreactive. At week 10, mild hepatocyte dysplasia and perivenular inflammation were evident, together with a corresponding increase in perivenular TGFα immunoreactivity. By week 16, foci of moderate to severe dysplasia were observed; at this stage, there was a decrease in perivenular immunoreactivity but a further increase in overall liver tissue TGFα levels. Some ‘altered foci’ and dysplastic nodules showed intense immunoreactivity for TGFα. At these time points, immunodetectable liver EGFr was found to decrease significantly in comparison with normal control tissue. TGFα immunoreactivity was observed in fully developed carcinomas at week 19, although some tumours were negative by immunohistochemistry. The up‐regulation of immunodetectable TGFα and the concomitant down‐regulation of EGFr demonstrated positive ( P <0·01) and negative ( P <0·001) correlations, respectively, with hepatocyte proliferation indices. These findings suggest that the TGFα/EGFr ligand receptor system may be important during tumour promotion and in the stimulation of continued proliferation in hepatocellular carcinomas.