Chronic activity of ectopic type I fibroblast growth factor receptor tyrosine kinase in prostate epithelium results in hyperplasia accompanied by intraepithelial neoplasia

摘要

BACKGROUND. Ectopic expression of fibroblast growth factor receptor 1 (FGFR1) tyrosine kinase in epithelial cells is associated with progression of prostate cancer. Ectopic expression by transfection of FGFR1 in premalignant epithelial cells from nonmalignant Dunning tumors accelerated time-dependent progression of epithelial cells to malignancy. This study was designed to test the effect of chronic androgen-dependent ectopic activity of FGFR1 in the normal adult mouse epithelium by gene targeting. MATERIALS AND METHODS. Constitutively active FGFR1 (caFGFR1) was targeted to prostate epithelial cells using the androgen-dependent probasin (PB) promoter. Prostate tissues of three strains were characterized over a period of 2 years by HE staining, immunohistochemical analyses for cytokeratin and a-actin, and rate of androgen-induced regeneration after castration. RESULTS. Relative to wildtype littermates, transgenic mice showed increased overall size, hyperplasia in epithelial, and, to a lesser extent, stromal compartments and nuclear atypia in epithelial cells of the prostate with increasing age. Androgen-induced regeneration after castration was enhanced at day 3 by two-fold in mice expressing ectopic caFGFR1. CONCLUSIONS. The ectopic presence and chronic activation of FGFR1 in mouse prostate epithelial cells induces progressive prostate intraepithelial neoplasia. These results confirm results suggested by the transplantable Dunning tumor and cell culture models that, in contrast to homeostasis-promoting resident FGFR2, chronic ectopic FGFR1 kinase activity in the epithelium disrupts homeostasis between stroma and epithelium. Although insufficient alone, it may cooperate with other oncogenic changes to promote epithelial cells down the path to malignancy. (C) 2004 Wiley-Liss, Inc.