FIBROBLAST GROWTH-FACTOR RECEPTOR-2 LIMITS AND RECEPTOR-1 ACCELERATESTUMORIGENICITY OF PROSTATE EPITHELIAL-CELLS

Progressive loss of the differentiated phenotype and communication wit h stroma accompanies the transition of nonmalignant rat prostate epith elial cells to anaplastic, malignant tumors. Here me show that cell su rface expression of the fibroblast growth factor receptor 2 (FGFR2) ty rosine kinase is reduced in malignant tumor cell populations (type TI) and undetectable at the mRNA level in 30% of cells, This is in additi on to the irreversible loss by splice switching of the FGFR2 ectodomai n that abrogates response to FGF-7 and homologues from the stroma, One hundred % of type II malignant cells express FGFR1, which is normally expressed in the stroma. Expression of the FGFR1 kinase in premaligna nt type I tumor epithelial cells by transfection accelerated progressi on to the malignant phenotype. In contrast to the FGFR2 kinase fused t o the ectodomain of FGFR1, the FGFR1 kinase failed initially to suppor t a mitogenic response to FGF-2 in type I tumor cells. However, the FG PR1-transfected cells acquired a mitogenic response after extensive pr oliferation of the cell population, Resident FGFR2 and ectopic FGFR1 a ppeared to be partitioned in the type I cells, because neither full-le ngth nor truncated isoforms of FGFR1 affected the mitogenic response o f the other, Restoration of the FGFR2IIIb kinase to malignant cells ex pressing FGFR1 depressed tumor growth rates, restored responsiveness t o stromal cells, and restored epithelial cell differentiation. These o bservations reveal that homologous FGFR1 and FGFR2 kinases play very d ifferent roles in cell growth and differentiation and in development a nd support of the malignant phenotype.