Disruption of fibroblast growth factor signal pathway inhibits the growth of synovial sarcomas: Potential application of signal inhibitors to molecular target therapy
Disruption of fibroblast growth factor signal pathway inhibits the growth of synovial sarcomas: Potential application of signal inhibitors to molecular target therapy
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DOI：
10.1158/1078-0432.ccr-04-2057
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发表时间：
2005-04-01
影响因子：
11.5
通讯作者：
Toguchida, J
中科院分区：
文献类型：
--
作者：
Ishibe, T;Nakayama, T;Toguchida, J
目的：滑膜肉瘤是一种软组织肉瘤，其生长调节机制尚不清楚。我们研究了滑膜肉瘤中成纤维细胞生长因子（FGF）信号的参与，并评估了抑制FGF信号的治疗效果。实验设计：采用逆转录-PCR方法分析了18种原发性滑膜肉瘤和5种滑膜肉瘤细胞系中22种FGF和4种FGF受体（FGFR）基因的表达。分析了重组FGF 2、FGF 8和FGF 18对丝裂原活化蛋白激酶（MAPK）活化和滑膜肉瘤细胞系生长的影响。结果：滑膜肉瘤细胞株表达多种FGF基因，尤其是在神经组织中表达的FGF基因，其中FGF 8在所有滑膜肉瘤细胞株中均表现出生长刺激作用。滑液肉瘤中的FGF信号诱导细胞外信号调节激酶（ERK 1/2）和p38 MAPK的磷酸化，但不诱导c-Jun NH 2末端激酶的磷酸化。FGFR的特异性抑制剂对滑膜肉瘤中FGF信号传导途径的破坏导致细胞周期停滞，导致体外和体内显著的生长抑制。FGFR抑制剂的生长抑制与磷酸化ERK 1/2的下调有关，但与p38 MAPK无关，ERK激酶抑制剂也显示出对滑膜肉瘤的生长抑制作用。结论：FGF信号在滑膜肉瘤的生长过程中起重要作用，抑制因子有望成为滑膜肉瘤分子靶向治疗的新靶点。
Purpose: Synovial sarcoma is a soft tissue sarcoma, the growth regulatory mechanisms of which are unknown. We investigated the involvement of fibroblast growth factor (FGF) signals in synovial sarcoma and evaluated the therapeutic effect of inhibiting the FGF signal.Experimental Design: The expression of 22 FGF and 4 FGF receptor (FGFR) genes in 18 primary tumors and five cell lines of synovial sarcoma were analyzed by reverse transcription-PCR. Effects of recombinant FGF2, FGF8, and FGF18 for the activation of mitogen-activated protein kinase (MAPK) and the growth of synovial sarcoma cell lines were analyzed. Growth inhibitory effects of FGFR inhibitors on synovial sarcoma cell lines were investigated in vitro and in vivo.Results: Synovial sarcoma cell lines expressed multiple FGF genes especially those expressed in neural tissues, among which FGF8 showed growth stimulatory effects in all synovial sarcoma cell lines. FGF signals in synovial sarcoma induced the phosphorylation of extracellular signal regulated kinase (ERK1/2) and p38MAPK but not c-Jun NH2-terminal kinase. Disruption of the FGF signaling pathway in synovial sarcoma by specific inhibitors of FGFR caused cell cycle arrest leading to significant growth inhibition both in vitro and in vivo, Growth inhibition by the FGFR inhibitor was associated with a down-regulation of phosphorylated ERK1/2 but not p38MAPK, and an ERK kinase inhibitor also showed growth inhibitory effects for synovial sarcoma, indicating that the growth stimulatory effect of FGF was transmitted through the ERK1/2.Conclusions: FGF signals have an important role in the growth of synovial sarcoma, and inhibitory molecules will be of potential use for molecular target therapy in synovial sarcoma.