Glioblastoma (GBM) is a highly invasive primary brain tumor that displays cellular heterogeneity, which is composed of glioma initiating cells (GICs) and their differentiated progeny. GICs play an important role in driving aggressive invasion. In particular, the interaction between GICs and blood vessels is critical because blood vessels are known to serve as routes for the invasion of GICs. However, the effect of endothelial cells on the three-dimensional (3D) invasion process of GICs as well as the spatial relationship between GICs and their differentiated progeny remains unclear. Here, we utilized a microfluidic device to recapitulate the 3D brain tumor microenvironments constituted by human umbilical vein endothelial cells (HUVECs) and type I collagen. Using the device, we found that HUVECs promoted the 3D invasion of heterogeneous glioma cell populations into type I collagen gel. The invasion induced by HUVECs was predominantly preceded by cells positive for nestin, a neural stem cell marker. In contrast, cells positive for tubulin β3 (TUBB3), a differentiated cell marker, rarely preceded invasion. In addition, HUVECs induced the upregulation of TUBB3 in GICs. Finally, we found that the genes associated with invasion, such as integrins α2 and β3, were significantly upregulated in the presence of HUVECs. These results as well as the experimental approach provide valuable knowledge for the development of effective therapeutic strategies targeting the aggressive invasion of GBM.

中文翻译：

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在微流体共培养平台中内皮诱导的异质性胶质瘤起始细胞的三维侵袭

胶质母细胞瘤（GBM）是一种高度侵袭性的原发性脑肿瘤，显示出细胞异质性，由胶质瘤起始细胞（GIC）及其分化后代组成。GIC在推动侵略性入侵方面发挥着重要作用。特别地，GIC与血管之间的相互作用至关重要，因为已知血管可作为GIC入侵的途径。然而，内皮细胞对GIC的三维（3D）侵袭过程以及GIC及其分化后代之间的空间关系的影响尚不清楚。在这里，我们利用微流控设备概括了由人脐静脉内皮细胞（HUVEC）和I型胶原蛋白构成的3D脑肿瘤微环境。使用设备，我们发现HUVEC促进了异种神经胶质瘤细胞群体3D侵袭到I型胶原凝胶中。HUVEC诱导的入侵主要发生在神经干细胞标记物Nestin阳性的细胞之前。相反，微管蛋白β3（TUBB3）（一种分化的细胞标志物）阳性的细胞很少出现在侵袭之前。此外，HUVEC诱导了GIC中TUBB3的上调。最后，我们发现在HUVEC存在下，与侵袭相关的基因（如整合素α2和β3）被显着上调。这些结果以及实验方法为开发针对性侵袭GBM的有效治疗策略提供了宝贵的知识。神经干细胞标记。相反，微管蛋白β3（TUBB3）（一种分化的细胞标志物）阳性的细胞很少出现在侵袭之前。此外，HUVEC诱导了GIC中TUBB3的上调。最后，我们发现在HUVEC存在下，与侵袭相关的基因（如整合素α2和β3）被显着上调。这些结果以及实验方法为开发针对性侵袭GBM的有效治疗策略提供了宝贵的知识。神经干细胞标记。相反，微管蛋白β3（TUBB3）（一种分化的细胞标志物）阳性的细胞很少出现在侵袭之前。此外，HUVEC诱导了GIC中TUBB3的上调。最后，我们发现在HUVEC存在下，与侵袭相关的基因（如整合素α2和β3）被显着上调。这些结果以及实验方法为开发针对性侵袭GBM的有效治疗策略提供了宝贵的知识。