FGFR2 gene mutation in human prostate cancer : Close relation to loss of hormone dependency and therapeutic application

成纤维细胞生长因子(FGFs)及其受体(FGFRs)在人类前列腺发育和动态平衡中促进间质-上皮细胞的通讯。对间质FGF7和FGF10有反应的驻留上皮细胞FGFR2IIIb的丢失伴随着模型动物和人类前列腺癌的恶性进展。我们研究了在恶性前列腺癌PC-3细胞系中通过转基因恢复FGFR2IIIb是否恢复了与较低恶性度肿瘤相关的细胞特性。FGFR2IIIb在PC-3细胞中的表达导致体外生长抑制，体内肿瘤形成减少，同时细胞分化和细胞凋亡增加。此外，我们还研究了辐射与FGFR2IIIb在PC-3细胞中的协同作用。辐射显著降低了PC-3细胞的克隆数。结果表明，将FGFR2IIIb修复到恶性人类前列腺上皮细胞原型PC-3中，可以恢复与非恶性肿瘤和正常细胞相关的特性。这进一步表明，上皮细胞驻留、促进动态平衡的FGFR2可能参与了对恶性肿瘤的抑制，修复可能是激素非依赖性前列腺癌基因治疗的候选基因。

Fibroblast growth factors (FGFs) and their receptors (FGFRs) expedite stromal-epithelial communication in development and homeostasis of the human prostate. Loss of resident epithelial cell FGFR2IIIb that responds to stromal FGF7 and FGF10 accompanies malignant progression of both model animal and human prostate tumors. We examined whether restoration of FGFR2IIIb by transfection in the malignant human prostate tumor PC-3 cell line restored cellular properties associated with less malignant tumors. Expression of FGFR2IIIb in PC-3 cells by transfection resulted in growth suppression in vitro and reduced tumor formation in vivo concurrent with increased cellular differentiation and apoptosis. Furthermore, we investigated the synergistic effects of radiation with the FGFR2IIIb in PC-3 cells. Radiation dramatically decreased the number of colonies in transfected PC-3 cells. The results indicate that restoration of FGFR2IIIb to the malignant human prostate epithelial cell prototype PC-3 restores properties associated with nonmalignant tumors and normal cells. This further suggests that epithelial cell resident, homeostasis-promoting FGFR2 may be involved in suppression of malignancy and that restoration may be a candidate for gene therapy of hormone-refractory prostate cancer.