Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments.
Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments.
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DOI：
10.1158/0008-5472.can-10-3026
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发表时间：
2011-08-15
期刊：
影响因子：
11.2
通讯作者：
Lawler SE
中科院分区：
文献类型：
--
作者：
Williams SP;Nowicki MO;Liu F;Press R;Godlewski J;Abdel-Rasoul M;Kaur B;Fernandez SA;Chiocca EA;Lawler SE
肿瘤的侵袭和增殖需要肿瘤细胞和内皮细胞的配合。糖原合成酶激酶 3 (GSK-3) 越来越被认为是调节侵袭和增殖的信号通路的主要贡献者。在这里，我们证明靛玉红家族的 GSK-3 抑制剂在体外和体内都能减少神经胶质瘤细胞和富含神经胶质瘤起始细胞的神经球的侵袭，并且我们表明 β-连环蛋白信号在介导这些作用中发挥着重要作用。靛玉红改善了患有神经胶质瘤的小鼠的存活率，在接受治疗的动物中观察到血管密度大幅下降。此外，靛玉红还能阻断内皮细胞的迁移，这表明体内使用GSK-3抑制剂进行抗侵袭性胶质瘤治疗不仅可以抑制肿瘤细胞的侵袭，还可以阻断内皮细胞的迁移，而内皮细胞的迁移也是肿瘤血管生成所必需的。总体而言，我们的研究结果表明，靛玉红对 GSK-3 的抑制提供了一种新的治疗范例，以靶向癌症异型模型中两个最重要的相互作用的细胞区室。
Invasion and proliferation in neoplasia require the cooperation of tumor cell and endothelial compartments. Glycogen synthase kinase-3 (GSK-3) is increasingly recognized as a major contributor to signaling pathways that modulate invasion and proliferation. Here we show that GSK-3 inhibitors of the indirubin family reduce invasion of glioma cells and glioma-initiating cell-enriched neurospheres both in vitro and in vivo, and we show that β-catenin signaling plays an important role in mediating these effects. Indirubins improved survival in glioma-bearing mice in which a substantial decrease in blood vessel density was seen in treated animals. In addition, indirubins blocked migration of endothelial cells, suggesting that anti-invasive glioma therapy with GSK-3 inhibitors in vivo not only inhibits invasion of tumor cells, but blocks migration of endothelial cells, which is also required for tumor angiogenesis. Overall, our findings suggest that indirubin inhibition of GSK-3 offers a novel treatment paradigm to target 2 of the most important interacting cellular compartments in heterotypic models of cancer.