Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma
Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma
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DOI：
10.1158/0008-5472.can-07-1316
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发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
Weiss, William A.
中科院分区：
文献类型：
--
作者：
Chesler, Louis;Goldenberg, David D.;Weiss, William A.
MYCN在神经嵴的靶向表达[在大鼠酪氨酸羟化酶（TH）启动子的控制下]导致转基因小鼠（TH-MYCN）中的神经母细胞瘤，并且是这种疾病的良好建立的模型。由于高水平的MYCN与神经母细胞瘤中增强的肿瘤血管生成和较差的临床结果相关，我们连续表征了这些动物肿瘤的恶性进展、血管生成和对血管生成阻断的敏感性。肿瘤细胞是增殖性的，分泌高水平的血管生成配体血管内皮生长因子（VEGF），并募集表达血管生成标志物VEGF-R2、α-SMA和基质金属蛋白酶MMP-2和MMP-9的复杂脉管系统，所有这些也在人类疾病中表达。用血管生成抑制剂TNP-470治疗已建立的小鼠肿瘤导致几乎完全消融，增殖减少，凋亡增强和血管破坏。由于TNP-470与神经毒性相关，我们测试了最近描述的水溶性HPMA共聚物-TNP-470缀合物（caplostatin），其显示出相当的功效并且耐受良好，没有体重减轻或神经毒性，如通过旋转棒测试所测量的。本研究强调了在具有天然肿瘤微环境相互作用的自发性小鼠肿瘤中血管生成抑制的重要性，验证了使用TH-MYCN转基因小鼠作为这种常见儿科肿瘤的治疗模型，并支持caplostatin作为儿童神经母细胞瘤抗血管生成治疗的进一步临床开发。
Targeted expression of MYCN to the neural crest [under control of the rat tyrosine hydroxylase (TH) promoter] causes neuroblastoma in transgenic mice (TH-MYCN) and is a well-established model for this disease. Because high levels of MYCN are associated with enhanced tumor angiogenesis and poor clinical outcome in neuroblastoma, we serially characterized malignant progression, angiogenesis, and sensitivity to angiogenic blockade in tumors from these animals. Tumor cells were proliferative, secreted high levels of the angiogenic ligand vascular endothelial growth factor (VEGF), and recruited a complex vasculature expressing the angiogenic markers VEGF-R2, alpha-SMA, and matrix metalloproteinases MMP-2 and MMP-9, all of which are also expressed in human disease. Treatment of established murine tumors with the angiogenesis inhibitor TNP-470 caused near-complete ablation, with reduced proliferation, enhanced apoptosis, and vasculature disruption. Because TNP-470 has been associated with neurotoxicity, we tested the recently described water-soluble HPMA copolymer-TNP-470 conjugate (caplostatin), which showed comparable efficacy and was well tolerated without weight loss or neurotoxicity as measured by rotarod testing. This study highlights the importance of angiogenesis inhibition in a spontaneous murine tumor with native tumor-microenvironment interactions, validates the use of mice transgenic for TH-MYCN as a model for therapy in this common pediatric tumor, and supports further clinical development of caplostatin as an antiangiogenic therapy in childhood neuroblastoma.