Endothelium-induced three-dimensional invasion of heterogeneous glioma initiating cells in a microfluidic coculture platform
Endothelium-induced three-dimensional invasion of heterogeneous glioma initiating cells in a microfluidic coculture platform
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DOI：
10.1039/c7ib00091j
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发表时间：
2017-09-01
影响因子：
2.5
通讯作者：
Sudo, Ryo
中科院分区：
文献类型：
--
作者：
Chonan, Yuta;Taki, Sotaro;Sudo, Ryo
胶质母细胞瘤（GBM）是一种高度侵袭性的原发性脑肿瘤，具有细胞异质性，由胶质瘤起始细胞（GIC）及其分化的子代细胞组成。GIC在驱动侵略性入侵方面发挥着重要作用。特别是，GIC和血管之间的相互作用是至关重要的，因为已知血管作为GIC侵入的途径。然而，内皮细胞对GIC三维（3D）侵袭过程的影响以及GIC及其分化后代之间的空间关系仍不清楚。在这里，我们利用微流控装置来重现由人脐静脉内皮细胞（HUVECs）和I型胶原蛋白构成的3D脑肿瘤微环境。使用该装置，我们发现HUVECs促进了异质性胶质瘤细胞群向I型胶原凝胶的3D侵袭。HUVECs诱导的侵袭主要是由神经干细胞标记物巢蛋白阳性的细胞引起的。相反，微管蛋白β 3（TUBB3）阳性的细胞，分化的细胞标志物，很少在入侵之前。此外，HUVECs诱导GIC中TUBB3的上调。最后，我们发现与侵袭相关的基因，如整合素α 2和β 3，在HUVECs存在下显著上调。这些结果以及实验方法为开发针对GBM侵袭性侵袭的有效治疗策略提供了有价值的知识。
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 beta 3 (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 alpha 2 and beta 3, 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.