PLATELET-ACTIVATING-FACTOR, AN ENDOGENOUS MEDIATOR OF INFLAMMATION, INDUCES PHENOTYPIC TRANSFORMATION OF RAT EMBRYO CELLS

The ability of platelet activating factor (PAF), a potent endogenous i nflammatory agent, to induce phenotypic transformation of primary rat embryo cells (RECs) was investigated. RECs are composed predominantly of fibroblasts, with some epithelial cells and a few neuronal and musc le cells. A 1 h period of treatment with PAF (1 X 10(-8)-1 X 10(-6) M) increased the ability of RECs to (i) form foci, (ii) reach a high sat uration density in complete medium, (iii) grow in low serum-containing medium and (iv) exhibit anchorage-independent (AI) growth. Similar ch anges were achieved with C-PAF (1 X 10(-10)-1 X 10(-8) M), an active, non-metabolizable analog of PAF, but not by lyso-PAF (1 X 10(-10)-1 X 10(-6) M), a biologically inactive metabolite of PAF. All of the PAF-i nduced phenotypic changes could be inhibited by pretreatment with a PA F receptor antagonist, CV3988 (1 X 10(-6) M). Pretreatment of RECs wit h genestein (1 mug/ml) also completely inhibited all four measures of PAF-induced REC transformation indicating that tyrosine kinase activit y may be required for the observed changes in phenotype. Pretreatment with indomethacin (2 x 10(-7) M) blocked the PAF-induced increases in focus formation and saturation density without affecting PAF-induced a lterations in growth in low serum or Al growth. This indicates that PA F may exert some of its effects through a cyclooxygenase product. Pret reatment with staurosporine (5 X 10(-8) M) failed to alter any of the PAF-induced effects, suggesting that protein kinase C activity is not involved in REC transformation by PAF. Our results provide the first e vidence that PAF, released by activated phagocytes in and around areas of inflammation, may contribute to the process of malignant transform ation.