Conditional activation of fibroblast growth factor receptor (FGFR) 1, but not FGFR2, in prostate cancer cells leads to increased osteopontin induction, extracellular signal-regulated kinase activation, and in vivo proliferation.
Conditional activation of fibroblast growth factor receptor (FGFR) 1, but not FGFR2, in prostate cancer cells leads to increased osteopontin induction, extracellular signal-regulated kinase activation, and in vivo proliferation.
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发表时间：
2003-10
期刊：
影响因子：
11.2
通讯作者：
K. Freeman;R. Gangula;B. Welm;M. Ozen;B. Foster;J. Rosen;M. Ittmann;N. Greenberg;D. Spencer
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文献类型：
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作者：
K. Freeman;R. Gangula;B. Welm;M. Ozen;B. Foster;J. Rosen;M. Ittmann;N. Greenberg;D. Spencer
成纤维细胞生长因子受体（FGFR）轴的变化通常与前列腺癌（CaP）进展相关。我们已经使用化学诱导二聚化（CID）来阐明FGFR 1和FGFR 2对肿瘤病因学的个体贡献。使用鼠前列腺的致瘤转基因腺癌（TRAMP）衍生的克隆TRAMP-C2 N（C2 N）制备稳定表达CID/AP 20187诱导型FGFR 1（iFGFR 1）和iFGFR 2的新型CaP细胞系，以产生C2N.iFGFR 1或C2N.iFGFR 2细胞。为了测试iFGFR活化对肿瘤生长的影响，将携带s.c. C2N.iFGFR1-或C2N.iFGFR2-衍生的肿瘤每两周用CID处理一次。iFGFR 1的激活导致肿瘤快速生长，这是增殖增加的结果。相反，iFGFR 2的表达抑制肿瘤生长。此外，我们已经确定，FGFR 1活化似乎在肿瘤发展的早期阶段是最重要的，但一旦建立，肿瘤迅速变得不依赖CID。在这些基于C2 N的细胞系中，在两种受体之间观察到定量信号传导差异，iFGFR 1导致更稳健的细胞外信号调节激酶活化。此外，iFGFR 1而非iFGFR 2的活化导致骨桥蛋白的强烈上调，骨桥蛋白是一种参与整合素活化并与CaP进展和转移相关的分泌型糖蛋白。这些研究支持这样的假设，即在哺乳动物中观察到的FGFR轴在CaP进展期间的变化具有重要的因果关系。
Changes in the fibroblast growth factor receptor (FGFR) axis are often associated with prostate cancer (CaP) progression. We have used chemically induced dimerization (CID) to elucidate the individual contributions of FGFR1 and FGFR2 to tumor etiology. Novel CaP cell lines stably expressing CID/AP20187-inducible FGFR1 (iFGFR1) and iFGFR2 were made using the tumorigenic transgenic adenocarcinoma of the murine prostate (TRAMP)-derived clone, TRAMP-C2N (C2N), to generate C2N.iFGFR1 or C2N.iFGFR2 cells. To test the effects of iFGFR activation on tumor growth, mice bearing s.c. C2N.iFGFR1- or C2N.iFGFR2-derived tumors were treated biweekly with CID. Activation of iFGFR1 led to rapid tumor growth as a result of increased proliferation. In contrast, expression of iFGFR2 inhibited tumor growth. Furthermore, we have ascertained that FGFR1 activation appears to be most important during the early stages of tumor development, but once established, tumors become rapidly CID independent. In these C2N-based lines, quantitative signaling differences were seen between the two receptors, with iFGFR1 leading to more robust extracellular signal-regulated kinase activation. Additionally, activation of iFGFR1, but not iFGFR2, led to strong up-regulation of osteopontin, a secreted glycoprotein involved in integrin activation and associated with CaP progression and metastasis. These studies support the hypothesis that observed changes in the FGFR axis in mammals during CaP progression are causally important.