title: Glioblastoma stem cells are regulated by interleukin-8 signaling in a tumoral perivascular niche.
abstract: Glioblastoma multiforme contains a subpopulation of cancer stem-like cells (CSC) believed to underlie tumorigenesis and therapeutic resistance. Recent studies have localized CSCs in this disease adjacent to endothelial cells (EC) in what has been termed a perivascular niche, spurring investigation into the role of EC-CSC interactions in glioblastoma multiforme pathobiology. However, these studies have been limited by a lack of in vitro models of three-dimensional disease that can recapitulate the relevant conditions of the niche. In this study, we engineered a scaffold-based culture system enabling brain endothelial cells to form vascular networks. Using this system, we showed that vascular assembly induces CSC maintenance and growth in vitro and accelerates tumor growth in vivo through paracrine interleukin (IL)-8 signaling. Relative to conventional monolayers, endothelial cells cultured in this three-dimensional system not only secreted enhanced levels of IL-8 but also induced CSCs to upregulate the IL-8 cognate receptors CXCR1 and CXCR2, which collectively enhanced CSC migration, growth, and stemness properties. CXCR2 silencing in CSCs abolished the tumor-promoting effects of endothelial cells in vivo, confirming a critical role for this signaling pathway in GMB pathogenesis. Together, our results reveal synergistic interactions between endothelial cells and CSCs that promote the malignant properties of CSCs in an IL-8-dependent manner. Furthermore, our findings underscore the relevance of tissue-engineered cell culture platforms to fully analyze signaling mechanisms in the tumor microenvironment.
authors.affiliation: Authors' Affiliations: Departments of Biomedical Engineering and Comparative Biomedical Sciences, Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, New York; Department of Veterinary Medicine, Colorado State University, Fort Collins, Colorado; and Laboratory for Translational Stem Cell Research, Weill Cornell Brain Tumor Center, Department of Neurological Surgery, Weill Cornell Medical College, New York.
authors.forename: David W
authors.initials: DW
authors.lastname: Infanger
authors.forename: YouJin
authors.initials: Y
authors.lastname: Cho
authors.forename: Brina S
authors.initials: BS
authors.lastname: Lopez
authors.forename: Sunish
authors.initials: S
authors.lastname: Mohanan
authors.forename: S Chris
authors.initials: SC
authors.lastname: Liu
authors.forename: Demirkan
authors.initials: D
authors.lastname: Gursel
authors.forename: John A
authors.initials: JA
authors.lastname: Boockvar
authors.forename: Claudia
authors.initials: C
authors.lastname: Fischbach
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D019899:Paracrine Communication / Q000502:physiology; D055153:Stem Cell Niche / Q000502:physiology*; D054457:Tissue Scaffolds; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D016209:Interleukin-8