BASIC RESEARCH OF NEW GENE THERAPY FOR PROSTATE CANCER WITH GROWTH FACTOR RECEPTOR

我们一直在研究成纤维细胞生长因子受体(FGFRs)在前列腺癌生长控制中的潜在作用。因此，我们最近发现，激素依赖型前列腺癌细胞表达FGFR2IIIb，FGFR2IIIb介导对间质来源的生长调节因子-7的反应，而在从激素依赖到激素非依赖性的过程中，它们失去了FGFR2IIIb的表达，从而逃避了FGFR2IIIb的生长调节。相反，激素非依赖性的前列腺癌细胞表达FGFR1并获得自主性。结果表明，FGFR2IIIb的恢复和FGFR1的失活都可能导致激素难治性前列腺癌的治疗。因此，我们通过转基因诱导了FGFR2IIIb在激素非依赖性大鼠前列腺癌细胞中的表达。结果，转基因细胞恢复了与基质的通讯，不仅表现出减慢的群体增长率，而且恢复了激素依赖肿瘤特有的细胞角蛋白表达和腺样形态。我们还将FGFR1基因导入激素非依赖性大鼠前列腺癌细胞，通过显性-负性作用使内源性FGFR1失活。结果表明，转基因细胞的体内生长与FGFR2IIIb导入的细胞相似。

We have been investigating the potential roles of fibroblast growth factor receptors (FGFRs) in growth control of prostate tumors. Consequently we have recently found that hormone-dependent prostate tumor cells express FGFR2IIIb which mediates response to stromal-derived growth regulator FGF-7, while they lose the expression of FGFR2IIIb during progression from hormone-dependent to hormone-independent and escape the growth regulation by FGF-7. Instead the hormone-independent prostate tumor cells express FGFR1 and acquire autonomy. The results indicate that both restoration of FGFR2IIIb and deactivation of FGFR1 may result in a treatment of hormone-refractory prostate cancer. Thus, we induced the expression of FGFR2IIIb in hormone-independent rat prostate tumor cells by transfection. As a result, the transfected cells regained communication with stroma and not only showed reduced population growth rates, but also recovered cytokeratin expression and gland-like morphology specific to hormone-dependent tumors. We also transfected hormone-independent rat prostate tumor cells with kinase-defective FGFR1 to deactivate the endogenous FGFR1 by dominant-negative effect. As a result, in vivo growth of the transfected cells was similar to that of FGFR2IIIb-introduced cells.