Treatment of human diploid fibroblasts at varying cell densities with 12-O-tetradecanoylphorbol-13-acetate (TPA) (10(-7) M) resulted in a bimodal response of proliferation rate: while at low cell densities (3 x 10(3)-1.5 x 10(4) cells/cm2) TPA inhibited the proliferation by up to 50%, at high cell densities (1-1.6 x 10(5) cells/cm2) a 2-fold higher proliferation rate as in untreated cultures was observed. When sparsely seeded normal diploid fibroblasts were grown in the presence of immobilized plasma membrane glycoproteins, as in confluent cell cultures strongly decreased proliferation and enhanced collagen type III synthesis is found. Using this test system, it emerged that the addition of plasma membrane proteins from untreated as well as from TPA-treated fibroblasts to untreated fibroblasts resulted in a strong inhibition of proliferation rate. In contrast, the addition of either untreated or TPA-treated plasma membrane proteins to cell cultured in the presence of TPA had no effect on growth. It is suggested that TPA treatment of normal diploid cells in culture results in a loss of responsiveness against cell-cell contacts, leading to an escape from the contact-dependent inhibition of growth.