Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma
Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma
复制标题
DOI：
10.3892/ijo_00000163
复制
发表时间：
2009-02-01
影响因子：
5.2
通讯作者：
Yamashiro, Darrell J.
中科院分区：
文献类型：
--
作者：
Zaghloul, Nibal;Hernandez, Sonia L.;Yamashiro, Darrell J.
大多数婴儿期后出现的神经母细胞瘤患儿都有转移性、耐药性疾病。MYCN原癌基因的扩增是这些预后不良的神经母细胞瘤肿瘤的重要标志。最近的研究表明，MYCN可能通过血管内皮生长因子（VEGF）促进血管生成。VEGF阻断已被证实是成人癌症的一种治疗策略。在这些研究中，我们询问在已建立的mycn扩增的神经母细胞瘤异种移植物中通过VEGFR2阻断来抑制VEGF信号是否会：1)限制肿瘤生长；2)诱导缺氧；3)改变肿瘤血管系统。将mycn扩增的人神经母细胞瘤细胞系NGP植入胸腺雌性小鼠。5周后，选择已确定肿瘤的小鼠，将一组小鼠安乐死作为第0天的对照组，其余小鼠每两周注射DC101（抗小鼠VEGFR2抗体）或载药。DC101治疗不能抑制已建立的NGP异种移植物的肿瘤进展性生长。虽然肿瘤血管没有明显破坏，但吡莫硝唑染色显示肿瘤缺氧适度增加，基因集富集分析（GSEA）显示，在dc101治疗的肿瘤中，先前描述的缺氧元基因表达增加。DC101诱导：1)VEGFR1及其配体胎盘生长因子表达增加；2)与Notch配体Jagged1的表达同时，肿瘤血管中Notch激活增加。这一结果表明，已建立的mycn扩增的神经母细胞瘤肿瘤相对不依赖于VEGF，并且显示出快速上调缺氧反应替代促血管生成机制的能力，当VEGF缺乏时，这种机制可能会稳定血管系统。
Most children with neuroblastoma presenting after infancy have metastatic, chemoresistant disease. Amplification of the MYCN proto-oncogene is a significant marker of these poor-prognosis neuroblastoma tumors. Recent studies suggest that MYCN may function in part by promoting angiogenesis via vascular endothelial growth factor (VEGF). VEGF blockade has been validated as a therapeutic strategy in adult cancers. In these studies, we asked whether inhibition of VEGF signaling via VEGFR2 blockade in established MYCN-amplified neuroblastoma xenografts would: 1) restrict tumor growth; 2) induce hypoxia; and 3) alter tumor vasculature. The MYCN-amplified neuroblastoma human cell line NGP was implanted intrarenally in athymic female mice. After 5 weeks, mice with established tumors were selected, a cohort euthanized to provide day 0 controls, and the rest assigned to receive biweekly injections of DC101 (anti-murine VEGFR2 antibody) or vehicle. DC101 treatment did not inhibit progressive tumor growth in established NGP xenografts. Although tumor vasculature was not significantly disrupted, a modest increase in tumor hypoxia was demonstrated by pimonidazole staining, and expression of a previously described hypoxia metagene was increased by gene set enrichment analysis (GSEA) in DC101-treated tumors. DC101 treatment elicited increased: 1) expression of VEGFR1 and its ligand placental growth factor; and 2) increased Notch activation in tumor vasculature concurrent with expression of the Notch ligand Jagged1. This result suggests that established MYCN-amplified neuroblastoma tumors are relatively VEGF-independent, and display the ability to rapidly up-regulate hypoxia-responsive alternative proangiogenic mechanisms that may stabilize vasculature when VEGF is deficient.