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Endothelium-induced three-dimensional invasion of heterogeneous glioma initiating cells in a microfluidic coculture platform

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Abstract

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.

Graphical abstract: Endothelium-induced three-dimensional invasion of heterogeneous glioma initiating cells in a microfluidic coculture platform

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Publication details

The article was received on 17 May 2017, accepted on 13 Jul 2017 and first published on 20 Jul 2017


Article type: Paper
DOI: 10.1039/C7IB00091J
Citation: Integr. Biol., 2017, Advance Article
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    Endothelium-induced three-dimensional invasion of heterogeneous glioma initiating cells in a microfluidic coculture platform

    Y. Chonan, S. Taki, O. Sampetrean, H. Saya and R. Sudo, Integr. Biol., 2017, Advance Article , DOI: 10.1039/C7IB00091J

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