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Regulation of Growth and Differentiation of Human Keratinocytes by Type ß Transforming Growth Factor and Epidermal Growth Factor¹

Departments of Medicine and Pharmacology, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510

The role of type ß transforming growth factor (TGFß) and epidermal growth factor (EGF) as regulators of the growth and differentiation of cultured human neonatal epidermal cells and squamous carcinoma cells was investigated in postconfluent cultures. Neither cell proliferation nor DNA synthesis was affected by treatment with TGFß alone; however, EGF significantly stimulated cell growth, and this process was specifically antagonized by TGFß. In addition, TGFß inhibited the maturation of human foreskin-derived epidermal cells, as measured by their competence to synthesize involucrin and to form cornified cell envelopes, in a dose-dependent manner. Although treatment with EGF did not affect the maturation of human foreskin-derived epidermal cells, the combination of a low concentration of TGFß with EGF resulted in significant enhancement of the maturation of these normal keratinocytes. Growth of three of four squamous carcinomas in the presence of EGF was not inhibited by TGFß. In addition, all four carcinomas were either totally or partially resistant to the induction of maturation by the combination of TGFß and EGF. This resistance of squamous carcinomas to TGFß was paralleled by an increased sensitivity to the antikeratinizing effects of EGF. Thus, TGFß inhibits the mitogenic stimulation of keratinocytes by EGF and induces cell maturation.

¹ Supported in part by USPHS Grants CA-08431 and CA-41556. M. R. is a recipient of a Swebilius Cancer Research Award.

² To whom requests for reprints should be addressed.

Received 7/23/86. Revised 5/28/87. Revised 9/ 3/87. Accepted 9/16/87.

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