Sal. Bennett et al., PLATELET-ACTIVATING-FACTOR, AN ENDOGENOUS MEDIATOR OF INFLAMMATION, INDUCES PHENOTYPIC TRANSFORMATION OF RAT EMBRYO CELLS, Carcinogenesis, 14(7), 1993, pp. 1289-1296
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.