Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition
Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition
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DOI：
10.1016/j.ccr.2007.11.004
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发表时间：
2007-12-01
期刊：
影响因子：
50.3
通讯作者：
Spencer, David M.
中科院分区：
文献类型：
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作者：
Acevedo, Victor D.;Gangula, Rama D.;Spencer, David M.
成纤维细胞生长因子受体-1（FGFR 1）通常在晚期前列腺癌（PCa）中过表达。为了研究因果关系，我们利用诱导型FGFR 1（iFGFR 1）前列腺小鼠模型。用化学二聚化诱导剂（CID）激活iFGFR 1导致高度同步、逐步进展为腺癌，其与上皮向间充质转化（EMT）有关。通过CID撤销的IFGFR 1失活导致前列腺上皮内瘤变的完全逆转，而PCa病变变得不依赖IFGFR 1。在肿瘤进展的不同阶段的基因表达谱显示EMT相关的Sox 9增加和Wnt信号通路的变化，包括Fzd 4，这在人类PCa中得到了验证。iFGFR 1模型清楚地表明FGFR 1参与了PCa进展，并证明了CID诱导模型如何有助于评估肿瘤进展和维持中的候选分子。
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.