Epidermal Growth Factor and Transforming Growth Factor α Stimulate or Inhibit Proliferation of a Human Renal Adenocarcinoma Cell Line Depending on Cell Status: Differentiation of the Two Pathways by G Protein Involvement¹

Transforming growth factor α production by renal tumors, acting through the epidermal growth factor receptor, has been implicated in malignant transformation by studies which compared gene expression in neoplastic and normal human tissue. We sought confirmation of this hypothesis by measuring the growth responses of a human renal tumor cell line to the addition of epidermal growth factor and transforming growth factor α. Surprisingly, it was found that both growth factors could induce either mitogenic or inhibitory signals depending on the growth status of the cultures. Confluent cultures were stimulated by both growth factors, and nonconfluent cultures were inhibited, as determined by thymidine incorporation, cell cycle analysis, and direct cell counting. These signals appear to use different transduction pathways, as growth factor induced inhibition was reversed by Bordetella pertussis toxin (which affects G protein signaling), whereas the stimulatory effects were not reversed. Two clones isolated from these cells responded in the same manner as the main cell isolate. These data show that the same cell may display opposite responses to equivalent conentrations of the same growth factor, depending on the transduction pathway used after triggering by receptor occupancy of either ligand (epidermal growth factor or transforming growth factor α).