INHIBITION OF GROWTH OF MALIGNANT RAT PROSTATE TUMOR-CELLS BY RESTORATION OF FIBROBLAST GROWTH-FACTOR RECEPTOR-2

A loss of expression of fibroblast growth factor (FGF) receptor 2 IIIb (FGFR2IIIb), which responds to stroma-derived FGF, accompanies progre ssion of premalignant androgen-responsive rat prostate tumor epithelia l cells to the malignant phenotype, Concurrently, the level of FGFR2 g ene expression is reduced and lost altogether in over 30% of cells, wh ereas all malignant cells abnormally express FGFR1, which is normally confined to stromal cells (S. Feng et al., Cancer Res., 57:5369-5378, 1997), To determine the relative roles of the FGFR2 and FGFR1 kinases in growth of malignant cells, we transfected malignant prostate epithe lial cells with the wild-type FGFR2IIIb kinase and an artificial chime ric construct (FGFR2IIIb/R1) composed of the FGFR2IIIb ectodomain and the FGFR1 kinase domain, Population growth kinetics, in both the absen ce and presence of FGF-7, which binds only the FGFR2IIIb ectodomain, w ere then examined in the transfected cell populations, In contrast to the untransfected malignant tumor cells and those expressing the FGFR2 IIIb/R1 chimera, FGF-7 caused a dose-dependent net inhibition of the p opulation growth rates of cells expressing the full-length FGFR2IIIb k inase, The results suggest that although the FGFR2 kinase can mediate positive mitogenic effects, it mediates a net restriction on the growt h of prostate tumor epithelial cells relative to FGFR1, Highly maligna nt prostate tumor cells, which have lost the FGFR2 tyrosine kinase, re tain the cellular response mechanisms to it, Restoration of the FGFR2 kinase to malignant tumors that are refractory to treatment may presen t a new avenue for gene therapy.