Evidence for activation of KIT, PDGFRα, and PDGFRβ receptors in the Ewing sarcoma family of tumors
Evidence for activation of KIT, PDGFRα, and PDGFRβ receptors in the Ewing sarcoma family of tumors
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DOI：
10.1002/cncr.22587
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发表时间：
2007-04-15
期刊：
影响因子：
6.2
通讯作者：
Pilotti, Silvana
中科院分区：
文献类型：
--
作者：
Bozzi, Fabio;Tamborini, Elena;Pilotti, Silvana
背景资料。尤文肉瘤家族(ESFT)是儿童和青少年最常见的恶性肿瘤之一，其特征是涉及尤文肉瘤(EWS)基因的非随机易位。多年来，强化多模式治疗方法的采用使EST患者的存活率逐渐提高。然而，高危患者的预后仍然不令人满意，新的治疗方法是可取的。本研究旨在探讨KIT、PDGFRα和PDGFRβ受体酪氨酸激酶(RTKs)在ESFT中的表达和激活情况。方法从20例冷冻ESFT标本中提取RNA和蛋白质，以确定KIT、PDGFRα和PDGFRβ的激活状态。定量聚合酶链式反应、免疫组织化学、免疫沉淀和/或Western印迹分析证实KIT、PDGFRα和PDGFRβ的表达和活化。特别是，与从正常成人组织获得的蛋白质池相比，PDGFRβ显示出更多的蛋白质表达和/或更强的磷酸化信号。结论：结果与试剂盒、PDGFRα和PDGFRβ受体的自分泌/旁分泌环激活一致，并提示了RTK抑制剂单独使用或与化疗联合使用的理论基础。
BACKGROUND. The Ewing sarcoma family of tumors (ESFT) is one of the most common malignant neoplasms of children and adolescents, characterized by nonrandom translocations involving the Ewing sarcoma (EWS) gene. Over the years the adoption of intensive multimodality treatment approaches has led to a gradual improvement in the survival of patients with EST. The prognosis is still unsatisfactory for high-risk patients, however, and novel therapeutic approaches are desirable. The aim of the study was to investigate the expression/activation of KIT, PDGFR alpha, and PDGFR beta receptor tyrosine kinases (RTKs) as potential therapeutic targets in ESFT.METHODS. RNA and proteins were extracted from 20 frozen ESFT specimens to ascertain the state activation of KIT, PDGFR alpha, and PDGFR beta.RESULTS. No mutations were found, whereas the cognate ligands were detected in all cases by polymerase chain reaction (PCR). The expression and activation of KIT, PDGFR alpha, and PDGFR beta were confirmed by quantitative PCR, immunohistochemistry, and immunoprecipitation and/or Western blot analysis. In particular, when compared with a protein pool obtained from normal adult tissues, PDGFR beta showed a greater protein expression and/or a stronger phosphorylation signal.CONCLUSIONS. The results are consistent with an autocrine/paracrine loop activation of the KIT, PDGFR alpha, and PDGFR beta receptors and suggest a rationale for the use of RTK inhibitors, either alone or in combination with chemotherapy.