EXON SWITCHING AND ACTIVATION OF STROMAL AND EMBRYONIC FIBROBLAST GROWTH-FACTOR (FGF)-FGF RECEPTOR GENES IN PROSTATE EPITHELIAL-CELLS ACCOMPANY STROMAL INDEPENDENCE AND MALIGNANCY

Stroma and the heparin-binding fibroblast growth factor (FGF) family i nfluence normal epithelial cell growth and differentiation in embryoni c and adult tissues. The role of stromal cells and the expression of i soforms of the FGF ligand and receptor family were examined during mal ignant progression of epithelial cells from a differentiated, slowly g rowing, nonmalignant model rat prostate tumor. In syngeneic hosts, a m ixture of stromal and epithelial cells resulted in nonmalignant tumors which were differentiated and slowly growing. In the absence of the s tromal cells, epithelial cells progressed to malignant tumors which we re independent of the stroma and undifferentiated. The independence of the malignant epithelial cells from stromal cells was accompanied by a switch from exclusive expression of exon IIIb to exclusive expressio n of exon IIIc in the FGF receptor 2 (FGF-R2) gene. The FGF-R2(IIIb) i soform displays high affinity for stromal cell-derived FGF-7, whereas the FGF-R2(IIIc) isoform does not recognize FGF-7 but has high affinit y for the FGF-2 member of the FGF ligand family. The switch from expre ssion of exclusively exon IIIb to exclusively exon IIIc in the residen t FGF-R2 gene was followed by activation of the FGF-2 ligand gene, the normally stromal cell FGF-R1 gene, and embryonic FGF-3 and FGF-5 liga nd genes in malignant epithelial cells. Multiple autocrine and potenti ally intracrine ligand-receptor loops resulting from these alterations within the FGF-FGF-R family may underlie the autonomy of malignant tu mor cells.