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Transforming Growth Factors Produced by Normal and Neoplastically Transformed Rat Liver Epithelial Cells in Culture¹

Department of Pathology, Montreal General Hospital and McGill University, Montreal, Quebec, H3G 1A4, Canada [C. L., M-S. T.] and Department of Pathology, University of North Carolina, Chapel Hill, North Carolina 27599-7525 [J. W. G.]

The secretion of transforming growth factors (TGFs) and ß 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-) 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 -glutamyl transpeptidase, secreted TGF--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-, even though they all expressed high levels of -glutamyl transpeptidase activity. When two of the non-TGF--secreting tumor cell lines were transplanted into isogeneic rats, the tumors that formed contained high levels of TGF--like activity. Although epidermal growth-factor (hence, TGF- 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--like activity, all cell lines/strains released TGF-ß activity into their conditioned media. However, while both normal or chemically transformed cell strains typically produced the inactive form of TGF-ß, the tumor cell lines tended to produce activated TGF-ß de novo. Anchorage-independent growth of cell lines that produced active TGF-ß was either stimulated, inhibited, or unaffected by TGF-ß. Cell lines that were inhibited by TGF-ß concurrently produced TGF- which was usually able to overcome the negative "autocrine" effect of TGF-ß. We conclude that both TGF- and TGF-ß, singly or in combination, are variously involved in the growth of transformed rat liver epithelial cells. TGF- has a predominantly positive autocrine action on the growth of rat liver epithelial tumor cell lines. The "paracrine" effect of TGF-ß may be at least as important as its autocrine effect in the growth of these transformed epithelial cell lines.

¹ Supported by grants from Medical Research Council of Canada [MA-9595 (M. S. T.)] and the NIH [CA29323 (J. W. G.)].

² Scholar of the Medical Research Council of Canada.

³ To whom requests for reprints should be addressed.

Received 5/28/87. Revised 11/ 6/87. Accepted 11/16/87.

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