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Cell Growth & Differentiation, Vol 6, Issue 3 251-261, Copyright © 1995 by American Association of Cancer Research


ARTICLES

Differential dependence of the tumorigenicity of chemically transformed rat liver epithelial cells on autocrine production of transforming growth factor alpha

SK Duddy, HS Earp, WE Russell, GJ Smith and JW Grisham
Department of Pathology, School of Medicine, University of North Carolina, Chapel Hill 27599, USA.

The tumorigenic phenotype in rat liver epithelial cells overexpressing c-myc may depend on a transforming growth factor (TGF)-alpha/epidermal growth factor receptor autocrine loop (L. W. Lee et al., Cancer Res., 51: 5238-5244, 1991). In the present study, we have used constitutive sense and antisense TGF-alpha expression vectors to modify TGF-alpha production in carcinogen-transformed clonal derivatives of a rat liver epithelial cell line, WB-F344, that variably express c-myc, endogenous TGF-alpha, and tumorigenicity. Transgene-mediated TGF-alpha protein production was elevated 2- to 9-fold in derivatives of a low c-myc-expressing transformed cell line, GN4, and 35-fold in a derivative of a high c-myc-expressing cell line, GN6. Although the GN4- and GN6-derived cell lines expressed functional EGF receptor and steady-state c-myc mRNA levels that were comparable to their respective parental cell lines, increased TGF-alpha expression did not increase the tumorigenicity of the derivatives relative to the parental cell lines. Similarly, in vitro growth characteristics of the GN4- and GN6-derived cell lines were not markedly altered by increased autocrine TGF-alpha production. Additionally, GN4, GN6, and their derivatives were, for the most part, unresponsive to exogenously applied TGF-alpha in vitro. In contrast, antisense TGF-alpha RNA expression significantly suppressed endogenous TGF-alpha production in a high c-myc-expressing, high TGF-alpha-expressing, highly tumorigenic clonal line, GP9; this suppression resulted in lowered steady-state c-myc levels and attenuated in vitro growth. Antisense-mediated suppression of all of these in vitro phenotypes in GP9 was reversed by exogenous TGF-alpha. The latency of tumor formation by the antisense derivative of cell line GP9 was significantly lengthened (> 3-fold) relative to the time required for tumor formation by its parental cell line. These results demonstrate that a TGF-alpha/epidermal growth factor receptor autocrine loop may be necessary for exaggerated in vitro and in vivo growth of some transformed rat liver epithelial cells (e.g., GP9); however, the autocrine loop is not generally sufficient to support tumorigenicity, even in transformed clonal lines expressing elevated levels of c-myc.





HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1995 by the American Association of Cancer Research.