Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA,
J Neurooncol. 2013 Nov;115(2):161-8. doi: 10.1007/s11060-013-1216-1. Epub 2013 Sep 12.
The Hedgehog (Hh) signaling pathway has been implicated in the most common childhood brain tumor, medulloblastoma (MB). Given the toxicity of post-surgical treatments for MB, continued need exists for new, targeted therapies. Based upon our finding that Neuropilin (Nrp) transmembrane proteins are required for Hh signal transduction, we investigated the role of Nrp in MB cells. Cultured cells derived from a mouse Ptch (+/-) ;LacZ MB (Med1-MB), effectively modeled the Hh pathway-related subcategory of human MBs in vitro. Med1-MB cells maintained constitutively active Hh target gene transcription, and consistently formed tumors within one month after injection into mouse cerebella. The proliferation rate of Med1-MBs in culture was dependent upon Nrp2, while reducing Nrp1 function had little effect. Knockdown of Nrp2 prior to cell implantation significantly increased mouse survival, compared to transfection with a non-targeting siRNA. Knocking down Nrp2 specifically in MB cells avoided any direct effect on tumor vascularization. Nrp2 should be further investigated as a potential target for adjuvant therapy in patients with MB.
刺猬（Hh）信号通路已被牵涉到最常见的儿童脑肿瘤，髓母细胞瘤（MB）。鉴于 MB 的手术后治疗的毒性，仍然需要新的靶向治疗。基于我们发现神经纤毛蛋白（Nrp）跨膜蛋白是 Hh 信号转导所必需的，我们研究了 Nrp 在 MB 细胞中的作用。从具有 Ptch（+/-）;LacZ 的小鼠衍生的培养细胞中，髓母细胞瘤（Med1-MB）有效地模拟了体外人类 MB 中与 Hh 途径相关的亚类。Med1-MB 细胞维持着持续活跃的 Hh 靶基因转录，并且在注入小鼠小脑后一个月内持续形成肿瘤。在培养物中 Med1-MB 的增殖速率取决于 Nrp2，而降低 Nrp1 功能的影响很小。在细胞植入前敲低 Nrp2 与转染非靶向性 siRNA 相比，显著增加了小鼠的存活率。特异性敲低 MB 细胞中的 Nrp2 避免了对肿瘤血管生成的任何直接影响。Nrp2 应作为 MB 患者辅助治疗的潜在靶点进行进一步研究。
