Abstract
The secretion of transforming growth factors (TGFs) α and β by normal, chemically transformed, and malignant rat liver epithelial cell lines was investigated. The WB-F344 normal cultured rat liver epithelial cell line does not secrete an epidermal growth factor-like (putatively TGF-α) activity, but several clonal cell strains derived from WB-F344 cells which had been treated with N-methyl-N′-nitro-N-nitrosoguanidine, especially those that expressed high levels of γ-glutamyl transpeptidase, secreted TGF-α-like activity into their conditioned media. Cell lines obtained from tumors which were produced by these cell strains varied in their abilities to secrete TGF-α, even though they all expressed high levels of γ-glutamyl transpeptidase activity. When two of the non-TGF-α-secreting tumor cell lines were transplanted into isogeneic rats, the tumors that formed contained high levels of TGF-α-like activity. Although epidermal growth-factor (hence, TGF-α also) inhibited the proliferation of several of these tumor cell lines in monolayer cultures, this growth factor often paradoxically stimulated the anchorage-independent growth of the same cell lines. In contrast to TGF-α-like activity, all cell lines/strains released TGF-β activity into their conditioned media. However, while both normal or chemically transformed cell strains typically produced the inactive form of TGF-β, the tumor cell lines tended to produce activated TGF-β de novo. Anchorage-independent growth of cell lines that produced active TGF-β was either stimulated, inhibited, or unaffected by TGF-β. Cell lines that were inhibited by TGF-β concurrently produced TGF-α which was usually able to overcome the negative “autocrine” effect of TGF-β. We conclude that both TGF-α and TGF-β, singly or in combination, are variously involved in the growth of transformed rat liver epithelial cells. TGF-α has a predominantly positive autocrine action on the growth of rat liver epithelial tumor cell lines. The “paracrine” effect of TGF-β may be at least as important as its autocrine effect in the growth of these transformed epithelial cell lines.
Supported by grants from Medical Research Council of Canada [MA-9595 (M. S. T.)] and the NIH [CA29323 (J. W. G.)].