Glioblastoma Stem Cells Are Regulated by Interleukin-8 Signaling in a Tumoral Perivascular Niche

Abstract

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.

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

“…Extensive work in solid tumors has shown that IL8 is critical in survival, invasion, and proliferation of cancer cells [21][22][23][24] and might be an important regulator of cancer stem cell activity. [25][26][27] Activation of multiple pathways by IL8, including phosphatidylinositol 3-kinase/protein kinase B (AKT), phospholipase C/protein kinase C, and mitogen-activated protein kinase (MAPK) signaling, leads to increased expression of various The online version of this article contains a data supplement.…”

Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs)

“…Therefore, IL8 could be a multifaceted inflammatory mediator used by the tumor to simultaneously promote angiogenesis (1,(3)(4)(5)(6)(7)(8)(9), co-opt immunosuppressive populations (1,(3)(4)(5)(6)(7)(8)(9), and disrupt the routes of migration of professional antigen-presenting dendritic cells (29).…”

“…IL8 does not only attract neutrophils but also monocytes to inflamed tissues (2). Tumor cells constitutively produce IL8 (2)(3)(4)(5)(6)(7)(8)(9) and hence plasma concentrations of IL8 reflect tumor burden (2) and determine prognosis (2)(3)(4)(5)(6)(7)(8)(9). IL8 is functional on CXCR1 and CXCR2 where it induces chemotactic responses.…”

Cerebrospinal fluid and serum IL-8, CCL2, and ICAM-1 concentrations in astrocytic brain tumor patients

“…GBM cells, which secrete IL-8, promote angiogenesis and microvascular endothelial permeability [9]. IL-8 can also regulate GBM associated Bcancer stem cells( CSCs) and was associated with tumor grade in astrocytic neoplasms [31]. IL-8 induces the growth and migration of CSCs via receptors CXCR1 and CXCR2.…”