Netrin-1 promotes medulloblastoma cell invasiveness and angiogenesis, and demonstrates elevated expression in tumor tissue and urine of patients with pediatric medulloblastoma.
Netrin-1 promotes medulloblastoma cell invasiveness and angiogenesis, and demonstrates elevated expression in tumor tissue and urine of patients with pediatric medulloblastoma.
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DOI：
10.1158/0008-5472.can-13-3116
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发表时间：
2014-07-15
期刊：
影响因子：
11.2
通讯作者：
Smith E
中科院分区：
文献类型：
--
作者：
Akino T;Han X;Nakayama H;McNeish B;Zurakowski D;Mammoto A;Klagsbrun M;Smith E
髓母细胞瘤（MB）在中枢神经系统内的侵袭和扩散是预测MB治疗失败和死亡的主要因素。Netrin-1是一种轴突导向因子，参与肿瘤和血管生物学，包括侵袭行为。我们发现，外源性netrin-1刺激人MB细胞和内皮细胞（EC）的侵袭，而VEGF-A，促进EC的侵袭，而不是MB细胞。此外，MB细胞沿着表达内源性netrin-1及其受体再生蛋白和UNC 5 B。内源性netrin-1、再生蛋白或UNC 5 B的阻断降低了MB的侵袭性。再生蛋白阻断剂抑制netrin-1诱导的EC管形成和EC向基质胶栓中的募集，这是血管生成的两个标志。在儿童MB患者中，与来自同一患者的对照标本相比，MB肿瘤标本中netrin-1 mRNA水平增加了1.7倍。免疫组织化学分析显示，netrin-1在MB肿瘤中比小脑对照升高。值得注意的是，MB患者的尿netrin-1水平是对照组的9倍。此外，与非侵袭性MB患者相比，侵袭性MB患者的尿netrin-1水平更高。最后，我们注意到MB切除术后患者的尿netrin-1水平降低。我们的研究结果表明netrin-1作为一种候选生物标志物，能够检测MB患者的侵袭性、播散性表型并预测其疾病状态。
Invasion and dissemination of medulloblastoma (MB) within the central nervous system is the principal factor predicting MB treatment failure and death. Netrin-1 is an axon guidance factor implicated in tumor and vascular biology, including in invasive behaviors. We found that exogenous netrin-1 stimulated invasion of human MB cells and endothelial cells (EC) in contrast to VEGF-A, which promoted invasion of EC but not MB cells. Further, MB cells expressed endogenous netrin-1 along with its receptors, neogenin and UNC5B. Blockades in endogenous netrin-1, neogenin or UNC5B reduced MB invasiveness. Neogenin blockade inhibited netrin-1-induced EC tube formation and recruitment of EC into Matrigel plugs, two hallmarks of angiogenesis. In pediatric MB patients, netrin-1 mRNA levels were increased 1.7-fold in MB tumor specimens compared to control specimens from the same patient. Immunohistochemical analyses showed that netrin-1 was elevated in MB tumors versus cerebellum controls. Notably, urinary levels of netrin-1 were 9-fold higher in MB patients compared to control individuals. Moreover, urinary netrin-1 levels were higher in patients with invasive MB compared to patients with non-invasive MB. Lastly, we noted that urinary netrin-1 levels diminished after MB resection in patients. Our results suggest netrin-1 as a candidate biomarker capable of detecting an invasive, disseminated phenotype in MB patients and predicting their disease status.