Directionally specific paracrine communication mediated by epithelial FGF9 to stromal FGFR3 in two-compartment premalignant prostate tumors
Directionally specific paracrine communication mediated by epithelial FGF9 to stromal FGFR3 in two-compartment premalignant prostate tumors
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DOI：
10.1158/0008-5472.can-03-3752
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发表时间：
2004-07-01
期刊：
影响因子：
11.2
通讯作者：
McKeehan, WL
中科院分区：
文献类型：
--
作者：
Jin, CL;Wang, F;McKeehan, WL
正常前列腺和非恶性二室前列腺肿瘤的组织稳态依赖于上皮和间质间室之间和谐的双向通讯。在成纤维细胞生长因子（FGF）家族内，从基质特异性FGF 7和FGF 10向上皮细胞特异性FGF受体（FGFR）2 IIIb-硫酸乙酰肝素复合物的信号传导在没有自分泌干扰的情况下从基质向上皮递送定向特异性指令。使用二室可移植前列腺肿瘤模型，其中基质细胞在体内的存活取决于上皮细胞，我们表明，从上皮细胞FGF 9到基质细胞FGFR 3的信号传导可能介导上皮细胞到基质细胞的通信，也是定向特异性的。FGF 9 mRNA仅在分化良好的二室Dunning R3327大鼠前列腺肿瘤的上皮细胞中表达。相反，FGFR 3仅在衍生的基质细胞中以功能上显著的水平表达。竞争结合和免疫沉淀分析显示，FGF 9仅与基质细胞上的FGFR结合。FGF 9也不能与表达FGFR 1和FGFR 2 IIIc的缺乏FGFR 3的基质细胞的克隆系共价交联。此外，FGF 9特异性刺激表达FGFR 3的基质细胞中的DNA合成。这些结果证明了来自上皮FGF 9和基质FGFR 3的定向特异性旁分泌信号传导。类似于从基质到上皮的FGF 7/FGF 10到wFGFR 2 IIIb信号传导，从上皮到基质的方向特异性似乎由同种型的细胞特异性表达和FGF的FGFR同种型的细胞环境特异性的组合设定。
Tissue homeostasis in normal prostate and two-compartment nonmalignant prostate tumors depends on harmonious two-way communications between epithelial and stromal compartments. Within the fibroblast growth factor (FGF) family, signaling to an epithelial cell-specific FGF receptor (FGFR) 2IIIb-heparan sulfate complex from stromal-specific FGF7 and FGF10 delivers directionally specific instruction from stroma to epithelium without autocrine interference. Using a two-compartment transplantable prostate tumor model in which survival of stromal cells in vivo depends on epithelial cells, we show that signaling from epithelial FGF9 to stromal FGFR3 potentially mediates epithelial-to-stromal communication that also is directionally specific. FGF9 mRNA was expressed exclusively in the epithelial cells derived from well-differentiated, two-compartment Dunning R3327 rat prostate tumors. In contrast, FGFR3 was expressed at functionally significant levels only in the derived stromal cells. Competition binding and immunoprecipitation assays revealed that FGF9 only bound to an FGFR on the stromal cells. FGF9 also failed to covalently cross-link to clonal lines of stromal cells devoid of FGFR3 that expressed FGFR1 and FGFR2IIIc. Furthermore, FGF9 specifically stimulated DNA synthesis in stromal cells expressing FGFR3. These results demonstrate a directionally specific paracrine signaling from epithelial FGF9 and stromal FGFR3. Similar to the FGF7/FGF10 to wFGFR2IIIb signaling from the stroma to the epithelium, the directional specificity from epithelium to stroma appears set by a combination of cell-specific expression of isoforms and cell-context specificity of FGFR isotypes for FGF.