Proliferation of human neuroblastomas mediated by the epidermal growth factor receptor
Proliferation of human neuroblastomas mediated by the epidermal growth factor receptor
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DOI：
10.1158/0008-5472.can-04-2426
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发表时间：
2005-11-01
期刊：
影响因子：
11.2
通讯作者：
Brodeur, GM
中科院分区：
文献类型：
--
作者：
Ho, R;Minturn, JE;Brodeur, GM
神经母细胞瘤是一种常见的儿童实体瘤，来源于神经嵴。表皮生长因子（EGF）受体（EGFR）的表达与其他肿瘤中细胞生长和侵袭行为的增强有关。在这里，我们研究了EGFR在神经母细胞瘤细胞系和原发性肿瘤中的表达谱。我们发现，所有13个神经母细胞瘤细胞系检查表达EGFR 1（HER 1），最容易检测到的水平。在几乎所有细胞系中也检测到低水平的其他人EGFR家族受体。所有检查的原发性肿瘤均表达可检测水平的HER 1和HER 3以及较低水平的HER 2和HER 4。EGF对体外培养的神经母细胞瘤细胞株的增殖有明显的促进作用。EGF（100 ng/mL）处理后细胞数明显增加（P < 0.01）。流式细胞术显示EGF可使更多的细胞进入S期和G（2）-M期，表明EGF通过促进细胞增殖而增加细胞数量，但对细胞凋亡无明显影响。EGF暴露导致受体自磷酸化和丝裂原活化蛋白激酶（MAPK）和磷酸肌醇3-激酶（PI 3 K）/AKT途径的激活。暴露于0.5 μ mol/L ZD 1839（一种HER 1特异性抑制剂），导致在含10%胎牛血清的培养基中生长的SY 5 Y和NLF细胞数量减少40%至50%（P < 0.01）。即使在0.01 μ mol/L时，ZD 1839也可抑制EGF引起的HER 1自磷酸化。在0.1 μ mol/L时，它也阻断NLF细胞中AKT的磷酸化，但不阻断MAPK的磷酸化。另外的研究表明，PI 3 K/AKT特异性抑制剂LY 294002在阻断EGF诱导的细胞增殖方面比MAPK特异性抑制剂U 0126具有更深远的作用。这表明PI 3 K/AKT通路是负责EGF在神经母细胞瘤中的增殖作用的主要信号通路。我们的研究结果还表明，ZD 1839是一种有效的神经母细胞瘤细胞增殖抑制剂，因此，它可能是一种有用的，基于生物学的治疗这些肿瘤的药物。
Neuroblastoma is a common solid tumor of childhood that is derived from the neural crest. Expression of epidermal growth factor (EGF) receptors (EGFRs) has been associated with enhanced cell growth and aggressive behavior in other tumors. Here, we examined the expression profile of EGFRs in neuroblastoma cell lines and primary tumors. We found that all 13 neuroblastoma cell lines examined expressed EGFR1 (HER1), most at readily detectable levels. Low levels of other human EGFR family receptors were also detected in almost all cell lines. All primary tumors examined expressed readily detectable levels of HER1 and HER3 and lower levels of HER2 and HER4. EGF had a significant effect on the proliferation of neuroblastoma cell lines in vitro. EGF treatment (100 ng/mL) of the cell lines SY5Y and NLF significantly increased cell number (P < 0.01). EGF stimulated more cells to enter S and G(2)-M phase, as suggested by flow cytometry, indicating that EGF increases cell number by increasing proliferation, with no appreciable change in apoptosis. EGF exposure resulted in receptor autophosphorylation and activation of both the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways. Exposure to 0.5 mu mol/L ZD1839, a HER1-specific inhibitor, caused a 40% to 50% reduction in the number of SY5Y and NLF cells grown in medium containing 10% fetal bovine serum (P < 0.01). Even at 0.01 mu mol/L, ZD1839 inhibited autophosphorylation of HER1 by EGF. At 0.1 mu mol/L, it also blocked phosphorylation of AKT, but not MAPK, in NLF cells. Additional studies showed that the PI3K/AKT-specific inhibitor LY294002 had a more profound effect than the MAPK-specific inhibitor U0126 in blocking EGF-induced cell proliferation. This suggests that the PI3K/AKT pathway is the main signaling pathway responsible for the proliferation effects of EGF in neuroblastomas. Our results also indicate that ZD1839 is a potent inhibitor of neuroblastoma cell proliferation; therefore, it may be a useful, biologically based therapeutic agent for these tumors.