Signaling of ERBB receptor tyrosine kinases promotes neuroblastoma growth in vitro and in vivo.
Signaling of ERBB receptor tyrosine kinases promotes neuroblastoma growth in vitro and in vivo.
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DOI：
10.1002/cncr.25073
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发表时间：
2010-07-01
期刊：
影响因子：
6.2
通讯作者：
Hughes, Dennis P. M.
中科院分区：
文献类型：
--
作者：
Richards, Kristen N.;Zweidler-McKay, Patrick A.;Van Roy, Nadine;Speleman, Frank;Trevino, Jesus;Zage, Peter E.;Hughes, Dennis P. M.
ERBB受体酪氨酸激酶可介导许多类型细胞的增殖、迁移、粘附、分化和存活，并在许多恶性肿瘤中发挥关键作用。最近的报道表明EGFR信号在神经母细胞瘤的增殖和存活中的作用，神经母细胞瘤是一种常见的儿科癌症，通常预后极差。我们通过流式细胞术、蛋白质印迹和Q-PCR检测了神经母细胞瘤细胞系和患者样本中ERBB家族的表达。通过细胞周期分析和蛋白质印迹法在体外评估对ERBB抑制的反应，并通过一系列肿瘤大小测量在体内评估对ERBB抑制的反应。一组神经母细胞瘤细胞系和原发性患者肿瘤表达EGFR、HER-3和HER-4，在一些肿瘤中表达Her-2。Her-4 mRNA主要以可裂解的亚型表达。虽然用厄洛替尼抑制EGFR和用CI-1033抑制pan-ERBB抑制EGF诱导的EGFR、AKT和ERK 1/2磷酸化，但仅CI-1033在体外诱导生长抑制和剂量依赖性细胞凋亡。CI-1033和厄洛替尼治疗神经母细胞瘤异种移植肿瘤均导致体内肿瘤生长减少，但CI-1033更有效。体内观察到EGFR主要在血管内皮细胞中表达。尽管EGFR在体内间接促进肿瘤生长，但Pan-ERBB抑制是体外ERBB相关神经母细胞瘤凋亡所必需的。内皮细胞中EGFR的抑制可能是厄洛替尼在体内对神经母细胞瘤生长影响的一个重要方面。我们的研究结果表明，非EGFR ERBB家族成员直接促进神经母细胞瘤的生长和存活，泛ERBB抑制代表了治疗神经母细胞瘤的潜在治疗靶点。
ERBB receptor tyrosine kinases can mediate proliferation, migration, adhesion, differentiation, and survival in many types of cells and play critical roles in many malignancies. Recent reports suggest a role for EGFR signaling in proliferation and survival of neuroblastoma, a common form of pediatric cancer that often has an extremely poor outcome. We examined ERBB family expression in neuroblastoma cell lines and patient samples by flow cytometry, western blot and Q-PCR. Response to ERBB inhibition was assessed in vitro by cell cycle analysis and western blot, and in vivo by serial tumor size measurements. A panel of neuroblastoma cell lines and primary patient tumors expressed EGFR, HER-3, and HER-4, with Her-2 in some tumors. Her-4 mRNA was expressed predominantly in cleavable isoforms. While EGFR inhibition with erlotinib and pan-ERBB inhibition with CI-1033 inhibited EGF-induced phosphorylation of EGFR, AKT, and ERK1/2, only CI-1033 induced growth inhibition and dose-dependent apoptosis in vitro. Both CI-1033 and erlotinib treatment of neuroblastoma xenograft tumors resulted in decreased tumor growth in vivo, though CI-1033 was more effective. In vivo expression of EGFR was observed predominantly in vascular endothelial cells. Pan-ERBB inhibition is required for ERBB-related neuroblastoma apoptosis in vitro, though EGFR contributes indirectly to tumor growth in vivo. Inhibition of EGFR in endothelial cells may be an important aspect of erlotinib's impact on neuroblastoma growth in vivo. Our results suggest that non-EGFR ERBB family members contribute directly to neuroblastoma growth and survival, and pan-ERBB inhibition represents a potential therapeutic target for treating neuroblastoma.
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影响因子：
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