Generation of Neuronal Progenitor Cells in Response to Tumors in the Human Brain
Generation of Neuronal Progenitor Cells in Response to Tumors in the Human Brain
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DOI：
10.1002/stem.1581
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发表时间：
2014-01-01
期刊：
影响因子：
5.2
通讯作者：
Momma, Stefan
中科院分区：
文献类型：
--
作者：
Macas, Jadranka;Ku, Min-Chi;Momma, Stefan
来自转基因小鼠模型的数据显示，神经元祖细胞（NPC）向实验性脑肿瘤迁移并调节病理过程。然而，NPC被吸引到CNS肿瘤的途径尚未完全了解，并且NPC是否向人类脑肿瘤（高级别星形细胞瘤）迁移尚未探索。我们分析了神经外科手术切除的肿瘤实质界面是否存在NPC，并将这些生理细胞与肿瘤块区分开来。我们观察到，聚唾液酸神经细胞粘附分子阳性的NPC聚集在高级别星形细胞瘤的边缘，并显示与不成熟的迁移性NPC一致的标志物。重要的是，这些高级别星形细胞瘤相关NPC不携带指示肿瘤的遗传畸变。此外，我们观察到NPC在CNS转移中积累。这些转移性肿瘤与神经细胞的区别在于确定的标志物集。将包埋在不渗透细胞的中空纤维囊中的鼠神经胶质瘤细胞移植到nestin-gfp报告小鼠的大脑中，表明扩散因子足以诱导神经原性反应。在体外，胶质瘤细胞分泌的血管内皮生长因子（VEGF）通过刺激VEGF受体-2（VEGFR-2）增加成人脑源性神经干细胞和祖细胞的迁移和增殖行为。在体内，用功能阻断抗体抑制VEGFR-2信号传导导致NPC向肿瘤的迁移减少。总的来说，我们的数据揭示了NPC被吸引到CNS肿瘤的机制，并表明NPC在人类高级别星形细胞瘤中积累。干细胞2014;32：244-257
Data from transgenic mouse models show that neuronal progenitor cells (NPCs) migrate toward experimental brain tumors and modulate the course of pathology. However, the pathways whereby NPCs are attracted to CNS neoplasms are not fully understood and it is unexplored if NPCs migrate toward brain tumors (high-grade astrocytomas) in humans. We analyzed the tumor-parenchyma interface of neurosurgical resections for the presence of (NPCs) and distinguished these physiological cells from the tumor mass. We observed that polysialic acid neural cell adhesion molecule-positive NPCs accumulate at the border of high-grade astrocytomas and display a marker profile consistent with immature migratory NPCs. Importantly, these high-grade astrocytoma-associated NPCs did not carry genetic aberrations that are indicative of the tumor. Additionally, we observed NPCs accumulating in CNS metastases. These metastatic tumors are distinguished from neural cells by defined sets of markers. Transplanting murine glioma cells embedded in a cell-impermeable hollow fiber capsule into the brains of nestin-gfp reporter mice showed that diffusible factors are sufficient to induce a neurogenic reaction. In vitro, vascular endothelial growth factor (VEGF) secreted from glioma cells increases the migratory and proliferative behavior of adult human brain-derived neural stem and progenitor cells via stimulation of VEGF receptor-2 (VEGFR-2). In vivo, inhibiting VEGFR-2 signaling with a function-blocking antibody led to a reduction in NPC migration toward tumors. Overall, our data reveal a mechanism by which NPCs are attracted to CNS tumors and suggest that NPCs accumulate in human high-grade astrocytomas. Stem Cells2014;32:244-257