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

The role of type β transforming growth factor (TGFβ) 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 TGFβ alone; however, EGF significantly stimulated cell growth, and this process was specifically antagonized by TGFβ. In addition, TGFβ 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 TGFβ 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 TGFβ. In addition, all four carcinomas were either totally or partially resistant to the induction of maturation by the combination of TGFβ and EGF. This resistance of squamous carcinomas to TGFβ was paralleled by an increased sensitivity to the antikeratinizing effects of EGF. Thus, TGFβ inhibits the mitogenic stimulation of keratinocytes by EGF and induces cell maturation.