Yan Guang-Ning, Yang Lang, Lv Yang-Fan, Shi Yu, Shen Li-Li, Yao Xiao-Hong, Guo Qiao-Nan, Zhang Peng, Cui You-Hong, Zhang Xia, Bian Xiu-Wu, Guo De-Yu
Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University and Key Laboratory of Tumour Immunopathology, Ministry of Education of China, Chongqing, 400038, People's Republic of China.
J Pathol. 2014 Sep;234(1):11-22. doi: 10.1002/path.4349. Epub 2014 Jun 18.
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.
癌症干细胞（CSCs）的微环境调节对癌症的发生和扩散有强烈影响。胶质瘤细胞与它们的微环境相互作用并获得CSCs表型的方式仍不清楚。我们研究了血管内皮细胞与胶质瘤细胞之间的通讯如何促进胶质瘤干细胞（GSCs）的特性。我们观察到在多形性胶质母细胞瘤（GBM）患者标本中，CD133(+) GSCs与Shh(+)内皮细胞紧密相邻。在体外和体内研究中，我们发现内皮细胞促进了CSC样胶质瘤细胞的出现，与内皮细胞共培养的胶质瘤细胞中，致瘤性增加以及干性基因如Sox2、Olig2、Bmi1和CD133的表达增加就证明了这一点。胶质瘤细胞中Smo的敲低导致其在体外和体内CSC样表型形成的显著减少。Shh敲低的内皮细胞未能促进共培养的胶质瘤细胞中Hedgehog（HH）信号通路的激活和CSC样表型的形成。通过检查65例患者的胶质瘤组织标本，我们发现胶质瘤患者的生存与内皮细胞中Shh的表达以及血管周围胶质瘤细胞中Gli1的表达密切相关。综上所述，我们的研究表明肿瘤微环境中的内皮细胞提供Shh以激活胶质瘤细胞中的HH信号通路，从而促进GSC特性和胶质瘤的增殖。
