Glioblastoma multiforme (GBM) contains a subpopulation of cancer stem-like cells (CSCs) believed to underlie tumorigenesis and therapeutic resistance. Recent studies have localized CSCs in this disease adjacent to endothelial cells (ECs) in what has been termed a perivascular niche, spurring investigation into the role of EC-CSC interactions in GBM 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 ECs to form vascular networks. Using this system, we demonstrated that vascular assembly induces CSC maintenance and growth in vitro and accelerates tumor growth in vivo through paracrine IL-8 signaling. Relative to conventional monolayers, ECs 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 ECs in vivo, confirming a critical role for this signaling pathway in GMB pathogenesis. Together, our results reveal synergistic interactions between ECs 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.

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