CD133⁺ and Nestin⁺ Glioma Stem-Like Cells Reside Around CD31⁺ Arterioles in Niches that Express SDF-1α, CXCR4, Osteopontin and Cathepsin K

Abstract

Poor survival of high-grade glioma is at least partly caused by glioma stem-like cells (GSLCs) that are resistant to therapy. GSLCs reside in niches in close vicinity of endothelium. The aim of the present study was to characterize proteins that may be functional in the GSLC niche by performing immunohistochemistry on serial cryostat sections of human high-grade glioma samples. We have found nine niches in five out of five high-grade glioma samples that were all surrounding arterioles with CD31+ endothelial cells and containing cellular structures that were CD133+ and nestin+. All nine niches expressed stromal-derived factor-1α (SDF-1α), its receptor C-X-C chemokine receptor type 4 (CXCR4), osteopontin and cathepsin K. SDF-1α plays a role in homing of CXCR4+ stem cells and leukocytes, whereas osteopontin and cathepsin K promote migration of cancer cells and leukocytes. Leukocyte-related markers, such as CD68, macrophage matrix metalloprotease-9, CD177 and neutrophil elastase were often but not always detected in the niches. We suggest that SDF-1α is involved in homing of CXCR4+ GSLCs and leukocytes and that cathepsin K and osteopontin are involved in the migration of GSLCs out of the niches.

Preclinical investigation of ibrutinib, a Bruton's kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes

“…For instance, the most studied stemness marker for a spectrum of cancer stem cells, particularly in GSCs, CD133 [4, 11], was significantly suppressed in the wake of Btk-silencing. Nestin, an important neural stem cell marker and EMT indicator, has been shown to be highly expressed in GBM patients with increased stemness and associated with a poor prognosis [16, 17]; Nestin was also significantly suppressed in Btk-silenced GBM cells. The down-regulation of Akt/mTOR pathway mediated by Btk-silencing and ibrutinib-treatment marks one of the most important observations in this study.…”

Perivascular niches as points of the utmost expression of tumor microenvironment

“…They are mostly absent in LGG or in mild infiltration areas of GB, but they become frequent after BBB disruption and the consequent starting of angiogenesis. Chemokines and their receptors largely take part in this process [27], among which CXCL12 (SDF-1)/ CXCR4, CX3CL1/CX3CR1 and CCL2/CCR2 are mainly involved, also in the niche function [8,38,39]. Of particular significance seems to be the expression of CXCL2 and VEGF in GAMs and of CXCR2 on endothelial cells that would indicate the angiogenic function of GAMs [11].…”

Proteases and cytokines as mediators of interactions between cancer and stromal cells in tumours

“…This cytokine then recruits hematopoietic progenitor cells from the bone marrow into the niche to create a metastasissupporting TME, which sustains metastatic cell growth (Kessenbrock et al, 2010). An example of proteases that contribute to cancer stem cell niche formation are MMPs and cathepsin K. The latter has been associated with periarteriolar stem cell niches where it co-localises with CXCL12/SDF-1α (Hira et al, 2015). This chemokine attracts glioblastoma cells into niches, where the cells become glioblastoma stem-like cells.…”