Acevedo Victor D, Gangula Rama D, Freeman Kevin W, Li Rile, Zhang Youngyou, Wang Fen, Ayala Gustavo E, Peterson Leif E, Ittmann Michael, Spencer David M
Program in Cell and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Cancer Cell. 2007 Dec;12(6):559-71. doi: 10.1016/j.ccr.2007.11.004.
Fibroblast Growth Factor Receptor-1 (FGFR1) is commonly overexpressed in advanced prostate cancer (PCa). To investigate causality, we utilized an inducible FGFR1 (iFGFR1) prostate mouse model. Activation of iFGFR1 with chemical inducers of dimerization (CID) led to highly synchronous, step-wise progression to adenocarcinoma that is linked to an epithelial-to-mesenchymal transition (EMT). iFGFR1 inactivation by CID withdrawal led to full reversion of prostatic intraepithelial neoplasia, whereas PCa lesions became iFGFR1-independent. Gene expression profiling at distinct stages of tumor progression revealed an increase in EMT-associated Sox9 and changes in the Wnt signaling pathway, including Fzd4, which was validated in human PCa. The iFGFR1 model clearly implicates FGFR1 in PCa progression and demonstrates how CID-inducible models can help evaluate candidate molecules in tumor progression and maintenance.
成纤维细胞生长因子受体1（FGFR1）在晚期前列腺癌（PCa）中通常过度表达。为了研究因果关系，我们使用了一种可诱导的FGFR1（iFGFR1）前列腺小鼠模型。用二聚体化学诱导剂（CID）激活iFGFR1会导致高度同步的、逐步进展为腺癌，这与上皮-间质转化（EMT）有关。通过停用CID使iFGFR1失活会导致前列腺上皮内瘤变完全逆转，而PCa病变则变得不依赖iFGFR1。在肿瘤进展的不同阶段进行基因表达谱分析，发现与EMT相关的Sox9增加，以及Wnt信号通路发生变化，包括Fzd4，这在人类PCa中得到了验证。iFGFR1模型清楚地表明FGFR1与PCa进展有关，并展示了CID诱导模型如何有助于评估肿瘤进展和维持过程中的候选分子。
