Cell Biology Program, Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
Cancer Res. 2011 Dec 1;71(23):7280-90. doi: 10.1158/0008-5472.CAN-11-1531. Epub 2011 Oct 11.
Glioblastoma multiforme is the most common glioma variant in adults and is highly malignant. Tumors are thought to harbor a subpopulation of stem-like cancer cells, with the bulk resembling neural progenitor-like cells that are unable to fully differentiate. Although multiple pathways are known to be involved in glioma tumorigenesis, the role of Wnt signaling has been poorly described. Here, we show that Dishevelled 2 (Dvl2), a key component of the Wnt signaling pathway, is overexpressed in human gliomas. RNA interference-mediated depletion of Dvl2 blocked proliferation and promoted the differentiation of cultured human glioma cell lines and primary, patient-derived glioma cells. In addition, Dvl2 depletion inhibited tumor formation after intracranial injection of glioblastoma cells in immunodeficient mice. Inhibition of canonical Wnt/β-catenin signaling also blocked proliferation, but unlike Dvl2 depletion, did not induce differentiation. Finally, Wnt5a, a noncanonical Wnt ligand, was also required for glioma cell proliferation. The data therefore suggest that both canonical and noncanonical Wnt signaling pathways downstream of Dvl2 cooperate to maintain the proliferative capacity of human glioblastomas.
多形性胶质母细胞瘤是成人中最常见的神经胶质瘤变体，恶性程度很高。肿瘤被认为存在一小部分类似于干细胞的癌细胞亚群，而大部分类似于无法完全分化的神经祖细胞样细胞。尽管已知有多种途径参与胶质瘤的肿瘤发生，但 Wnt 信号通路的作用描述甚少。在这里，我们表明，Wnt 信号通路的关键组成部分 Dishevelled 2（Dvl2）在人类神经胶质瘤中过度表达。通过 RNA 干扰介导的 Dvl2 耗竭阻断了培养的人类神经胶质瘤细胞系和原代、患者来源的神经胶质瘤细胞的增殖，并促进了其分化。此外，Dvl2 耗竭抑制了免疫缺陷小鼠颅内注射胶质母细胞瘤细胞后的肿瘤形成。经典 Wnt/β-catenin 信号通路的抑制也阻断了增殖，但与 Dvl2 耗竭不同，它没有诱导分化。最后，非经典 Wnt 配体 Wnt5a 也需要神经胶质瘤细胞的增殖。因此，数据表明，Dvl2 下游的经典和非经典 Wnt 信号通路协同作用，维持人类胶质母细胞瘤的增殖能力。
