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Growth Stimulation, Altered Regulation of Epidermal Growth Factor Receptors, and Autocrine Transformation of Spontaneously Transformed Normal Rat Kidney Cells by Transforming Growth Factor ß¹

Graduate Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02254 [M. A. N., E. A. L., M. J. N.], and Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 [J. K-O., H. L. M.]

The tumorigenic NRK-PT14 cell line requires exogenous epidermal growth factor (EGF), but has lost the requirement for transforming growth factor ß (TGF-ß) for anchorage-independent growth, compared to normal rat kidney (NRK) cells. Development of an optimized serum-free medium for the growth of these cells revealed that NRK-PT14 cells also exhibit a qualitatively altered sensitivity to exogenous type 1 TGF-ß, compared to NRK cells. EGF-induced serum-free monolayer growth of NRK-PT14 cells was stimulated 2-fold by TGF-ß under conditions where growth of NRK cells was inhibited by 67%. TGF-ß only stimulated the growth of NRK-PT14 cells when EGF was present and when EGF was added before TGF-ß. In addition, the stimulation of EGF-induced NRK-PT14 cell growth by TGF-ß was associated with a specific, reversible loss of the high-affinity subpopulation of EGF receptors from the surface of these cells. Treatment of NRK cells with TGF-ß resulted in an increase in this EGF receptor population. Finally, EGF-induced anchorage-independent growth of NRK-PT14 cells was shown to be dependent on secreted TGF-ß, demonstrating an autocrine role for TGF-ß in the transformed phenotype of these cells. Autocrine transformation of NRK-PT14 cells by TGF-ß may result directly from the acquisition of an altered (positive) sensitivity to this growth factor.

¹ This work was supported in part by Grants BC-483 from the American Cancer Society and BRSG S07 RR07044 from the Biomedical Research Support Grant Program of the NIH.

² Present address: Department of Virology, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland.

³ Recipient of a Junior Faculty Research Award from the American Cancer Society. Present address: Roche Institute of Molecular Biology, Roche Research Center, Nutley, NJ 07110. To whom requests for reprints should be addressed.

Received 12/ 1/88. Revised 3/10/89. Accepted 4/12/89.

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