title: Endothelial cells promote stem-like phenotype of glioma cells through activating the Hedgehog pathway.
abstract: 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.
authors.affiliation: 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.
authors.forename: Guang-Ning
authors.initials: GN
authors.lastname: Yan
authors.forename: Lang
authors.initials: L
authors.lastname: Yang
authors.forename: Yang-Fan
authors.initials: YF
authors.lastname: Lv
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Shen
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Yao
authors.forename: Qiao-Nan
authors.initials: QN
authors.lastname: Guo
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: You-Hong
authors.initials: YH
authors.lastname: Cui
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
authors.forename: De-Yu
authors.initials: DY
authors.lastname: Guo
mesh_terms: D000071916:AC133 Antigen; D064591:Allografts; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000473:pathology*; D005910:Glioma / Q000473:pathology*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D055153:Stem Cell Niche; D059016:Tumor Microenvironment
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D053823:Hedgehog Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; C509239:SHH protein, human
keywords: endothelial cell; glioma stem cell; hedgehog pathway; niche