Endothelial cells promote stem-like phenotype of glioma cells through activating the Hedgehog pathway

Microenvironmental regulation of cancer stem cells (CSCs) strongly influences the onset and spread of cancer. The way in which glioma cells interact with their microenvironment and acquire the phenotypes of CSCs remains elusive. We investigated how communication between vascular endothelial cells and glioma cells promoted the properties of glioma stem cells (GSCs). We observed that CD133(+) GSCs were located closely to Shh(+) endothelial cells in specimens of human glioblastoma multiforme (GBM). In both in vitro and in vivo studies, we found that endothelial cells promoted the appearance of CSC-like glioma cells, as demonstrated by increases in tumourigenicity and expression of stemness genes such as Sox2, Olig2, Bmi1 and CD133 in glioma cells that were co-cultured with endothelial cells. Knockdown of Smo in glioma cells led to a significant reduction of their CSC-like phenotype formation in vitro and in vivo. Endothelial cells with Shh knockdown failed to promote Hedgehog (HH) pathway activation and CSC-like phenotype formation in co-cultured glioma cells. By examination of glioma tissue specimens from 65 patients, we found that the survival of glioma patients was closely correlated with the expression of both Shh by endothelial cells and Gli1 by perivascular glioma cells. Taken together, our study demonstrates that endothelial cells in the tumour microenvironment provide Shh to activate the HH signalling pathway in glioma cells, thereby promoting GSC properties and glioma propagation. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.