Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing's sarcoma cells
Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing's sarcoma cells
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DOI：
10.1038/sj.onc.1206330
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发表时间：
2003-04-17
期刊：
影响因子：
8
通讯作者：
Toretsky, JA
中科院分区：
文献类型：
--
作者：
Üren, A;Merchant, MS;Toretsky, JA
尤文氏肉瘤家族肿瘤（ESFT）含有易位t（11;22），其导致新的致癌融合蛋白EWS/FLI 1。血小板源性生长因子（PDGF）及其受体（PDGFR）参与许多实体瘤的诱导和增殖，是新型靶向抗肿瘤治疗的潜在候选者。由于PDGF-C和EWS/FLI 1之间的关系被报道，我们试图表征ESFT中的PDGF信号通路。发现9个ESFT细胞中的8个表达显著水平的β-PDGFR。有趣的是，测试的细胞系均不表达α-PDGFR，其是PDGF-C结合所需的受体同种型。通过免疫组织化学染色，52例ESFT患者的存档肿瘤样本中有47例（90.4%）β-PDGFR阳性。用PDGF-AA或PDGF-BB配体处理ESFT细胞系以评估下游信号传导。仅在表达β-PDGFR的PDGF-BB刺激的细胞中检测到β-PDGFR的自磷酸化和PLC-γ、PI 3 Kp 85和She的酪氨酸磷酸化。使用趋化性测定进一步评价受体功能，所述趋化性测定显示TC-32细胞向PDGF-BB迁移。特异性PDGFR激酶抑制剂AG 1295阻断β-PDGFR激活、下游信号传导、细胞培养物中的生长和TC-32细胞的趋化性。AG 1295还在ESFT动物模型中延迟肿瘤形成并延长存活。我们的结论是，ESFT表达β-PDGFR，这是一个功能和潜在的关键信号通路。因此，β-PDGFRs可能为ESFT提供一种新的治疗靶点，可用于设计更好的治疗方式。
The Ewing's sarcoma family of tumors (ESFT) contain a translocation, t(11;22), which results in the novel oncogenic fusion protein EWS/FLI1. Platelet-derived growth factors (PDGF) and their receptors (PDGFR) are involved in the induction and proliferation of numerous solid tumors and are the potential candidates for novel targeted antitumor therapy. Since a relation was reported between PDGF-C and EWS/FLI1, we sought to characterize the PDGF signaling pathway in ESFT. Eight out of nine ESFT cell tines were found to express significant levels of beta-PDGFR. Interestingly, none of the tested cell lines expressed alpha-PDGFR, which is the receptor isotype required for PDGF-C binding. By immunohistochemical staining 47 of 52 (90.4%) archival tumor samples from patients with ESFT were positive for beta-PDGFR. ESFT cell lines were treated with PDGF-AA or PDGF-BB ligands to evaluate downstream signaling. Autophosphorylation of beta-PDGFR and tyrosine phosphorylation of PLC-gamma, PI3Kp85 and She were detected only in PDGF-BB-stimulated cells that express beta-PDGFR. Receptor function was further evaluated using chemotaxis assays that showed TC-32 cell migration towards PDGF-BB. A specific PDGFR kinase inhibitor AG1295 blocked beta-PDGFR activation, downstream signaling, growth in cell culture and chemotaxis of TC-32 cells. AG1295 also delayed tumor formation and prolonged survival in an ESFT animal model. We conclude that ESFT express beta-PDGFR and that this is a functional and potentially crucial signaling pathway. Therefore, beta-PDGFRs may provide a novel therapeutic target in ESFT that can be utilized to design better treatment modalities.