Glioblastoma stem cells are regulated by interleukin-8 signaling in a tumoral perivascular niche

David W. Infanger, YouJin Cho, Brina S. Lopez, Sunish Mohanan, S. Chris Liu, Demirkan Gursel, John A. Boockvar, Claudia Fischbach*

*Corresponding author for this work

Research output: Contribution to journalArticle

103 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7079-7089
Number of pages11
JournalCancer Research
Volume73
Issue number23
DOIs
StatePublished - Dec 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Infanger, D. W., Cho, Y., Lopez, B. S., Mohanan, S., Liu, S. C., Gursel, D., Boockvar, J. A., & Fischbach, C. (2013). Glioblastoma stem cells are regulated by interleukin-8 signaling in a tumoral perivascular niche. Cancer Research, 73(23), 7079-7089. https://doi.org/10.1158/0008-5472.CAN-13-1355