Department of Pediatrics, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.
Department of Life Science, National Taiwan University, Taipei, Taiwan.
Sci Rep. 2017 Sep 11;7(1):11212. doi: 10.1038/s41598-017-11637-8.
Neuroblastoma (NB) is a childhood cancer with a low survival rate and great metastatic potential. Vascular endothelial growth factor (VEGF), an angiogenesis factor, has been found to be involved in CRT-related neuronal differentiation of NB cells. In this study, we further confirmed the role VEGF in NB through mouse xenograft model and clinical analysis from NB patients. In xenograft experiments, CRT overexpression effectively inhibited the tumor growth. In addition, the mRNA and protein levels of VEGF and differentiation marker GAP-43 were upregulated by induced CRT expression. However, no significant correlation between the expression level of VEGF and microvessel density was observed in human NB tumors, suggesting a novel mechanism of VEGF participating in NB tumorigenesis through an angiogenesis-independent pathway. In NB patients' samples, mRNA expression levels of CRT and VEGF were positively correlated. Furthermore, positive VEGF expression by immunostaining of NB tumors was found to correlate well with histological grade of differentiation and predicted a favorable prognosis. In conclusion, our findings suggest that VEGF is a favorable prognostic factor of NB and might affect NB tumor behavior through CRT-driven neuronal differentiation rather than angiogenesis that might shed light on a novel therapeutic strategy to improve the outcome of NB.
神经母细胞瘤（NB）是一种儿童期癌症，其存活率低且具有很强的转移潜力。血管内皮生长因子（VEGF）是一种血管生成因子，已被发现参与 NB 细胞与 CRT 相关的神经元分化。在这项研究中，我们通过小鼠异种移植模型和 NB 患者的临床分析进一步证实了 VEGF 在 NB 中的作用。在异种移植实验中，CRT 的过表达有效地抑制了肿瘤的生长。此外，VEGF 和分化标志物 GAP-43 的 mRNA 和蛋白水平在 CRT 表达诱导下上调。然而，在人类 NB 肿瘤中，VEGF 的表达水平与微血管密度之间没有观察到显著的相关性，这表明 VEGF 通过一种血管生成非依赖途径参与 NB 肿瘤发生的新机制。在 NB 患者的样本中，CRT 和 VEGF 的 mRNA 表达水平呈正相关。此外，NB 肿瘤免疫组化的 VEGF 阳性表达与组织学分化程度密切相关，并预测预后良好。总之，我们的研究结果表明，VEGF 是 NB 的一个有利的预后因素，它可能通过 CRT 驱动的神经元分化而不是血管生成来影响 NB 肿瘤的行为，这可能为改善 NB 的治疗结果提供新的治疗策略。
