Frizzled 4 Regulates Stemness and Invasiveness of Migrating Glioma Cells Established by Serial Intracranial Transplantation
Frizzled 4 Regulates Stemness and Invasiveness of Migrating Glioma Cells Established by Serial Intracranial Transplantation
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DOI：
10.1158/0008-5472.can-10-1495
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发表时间：
2011-04-15
期刊：
影响因子：
11.2
通讯作者：
Kim, Hyunggee
中科院分区：
文献类型：
--
作者：
Jin, Xun;Jeon, Hee-Young;Kim, Hyunggee
多形性胶质母细胞瘤（GBM）最有害的特征之一是细胞侵袭性，这被认为是肿瘤复发的潜在原因。浸润的GBM细胞难以通过手术和局部治疗方式完全根除。虽然许多努力都集中在了解各种机制控制GBM的侵袭性，其性质仍然知之甚少。在本研究中，我们建立了高度连续的颅内移植。U87 R4细胞具有高度侵袭性，与非侵袭性但增殖性的U87 L4细胞相比，U87 R4细胞表现出干细胞样特性。连续移植过程中的微阵列分析显示，凋亡诱导基因（半胱天冬酶3和PDCD 4）下调，而几个癌症干细胞相关基因[卷曲4（FZD 4）和CD 44]在更具侵袭性的细胞中上调。U87 R4细胞对抗癌药物诱导的细胞死亡具有抵抗力，部分原因是caspase 3和PDCD 4的下调，并且由于Frizzled 4的上调，它们保留了激活的Wnt/β-连环蛋白信号传导，这足以控制神经球的形成。我们还发现，FZD 4促进上皮向间充质转化调节因子SNAI 1的表达，沿着间充质表型的获得。综上所述，我们的研究结果表明，卷曲4是Wnt信号家族的成员，该家族控制胶质瘤干细胞的干细胞性和侵袭性，并且它可能是GBM复发和预后不良的主要原因。Cancer Res; 71（8）; 3066-75. (C)2011年AACR。
One of the most detrimental hallmarks of glioblastoma multiforme (GBM) is cellular invasiveness, which is considered a potential cause of tumor recurrence. Infiltrated GBM cells are difficult to completely eradicate surgically and with local therapeutic modalities. Although much effort has focused on understanding the various mechanisms controlling GBM invasiveness, its nature remains poorly understood. In this study, we established highly serial intracranial transplantation. U87R4 cells were highly invasive and displayed stem cell-like properties, as compared to noninvasive but proliferative U87L4 cells. Microarray analysis during serial transplantation revealed that apoptosis-inducing genes (caspase3 and PDCD4) were downregulated whereas several cancer stem cell-relevant genes [Frizzled 4 (FZD4) and CD44] were upregulated in more invasive cells. U87R4 cells were resistant to anticancer drug-induced cell death, partly due to downregulation of caspase3 and PDCD4, and they retained activated Wnt/beta-catenin signaling due to upregulation of Frizzled 4, which was sufficient to control neurosphere formation. We also found that FZD4 promoted expression of the epithelial to mesenchymal transition regulator SNAI1, along with acquisition of a mesenchymal phenotype. Taken together, our results argue that Frizzled 4 is a member of the Wnt signaling family that governs both stemness and invasiveness of glioma stem cells, and that it may be a major cause of GBM recurrence and poor prognosis. Cancer Res; 71(8); 3066-75. (C) 2011 AACR.