The CXCR2/CXCL2 signalling pathway – An alternative therapeutic approach in high-grade glioma

Acker, Güliz; Zollfrank, Julia; Jelgersma, Claudius; Nieminen-Kelhä, Melina; Kremenetskaia, Irina; Mueller, Susanne; Ghori, Adnan; Vajkoczy, Peter; Brandenburg, Susan

doi:10.1016/j.ejca.2019.12.005

Cited by 35 publications

(57 citation statements)

References 34 publications

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“…Those factors have been shown to promote angiogenesis in other tumor models [46,47]. Accordingly, recent data elucidated that blocking of CXCR2, the main receptor for CXCL2 and IL8, led to reduced tumor sizes and diminished vascularization in a mouse glioma model [48]. Moreover, IL8 was found to be overexpressed by glioma cells if animals were treated with anti-angiogenic agents [49].…”

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confidence: 99%

Microglia/macrophages express alternative proangiogenic factors depending on granulocyte content in human glioblastoma

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Kremenetskaia

Urbantat

et al. 2020

The Journal of Pathology

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Myeloid cells are an inherent part of the microenvironment of glioblastoma multiforme (GBM). There is growing evidence for their participation in mechanisms of tumor escape, especially in the development of resistance following initially promising anti‐VEGF/VEGFR treatment. Thus, we sought to define the capability of myeloid cells to contribute to the expression of proangiogenic molecules in human GBM. We investigated GBM specimens in comparison with anaplastic astrocytoma (WHO grade III) and epilepsy patient samples freshly obtained from surgery. Flow cytometric analyses revealed two distinct CD11b+CD45+ cell populations in GBM tissues, which were identified as microglia/macrophages and granulocytes. Due to varied granulocyte influx, GBM samples were subdivided into groups with low (GBM‐lPMNL) and high (GBM‐hPMNL) numbers of granulocytes (polymorphonuclear leukocytes; PMNL), which were related to activation of the microglia/macrophage population. Microglia/macrophages of the GBM‐lPMNL group were similar to those of astrocytoma specimens, but those of GBM‐hPMNL tissues revealed an altered phenotype by expressing high levels of CD163, TIE2, HIF1α, VEGF, CXCL2 and CD13. Although microglia/macrophages represented the main source of alternative proangiogenic factors, additionally granulocytes participated by production of IL8 and CD13. Moreover, microglia/macrophages of the GBM‐hPMNL specimens were highly associated with tumor blood vessels, accompanied by remodeling of the vascular structure. Our data emphasize that tumor‐infiltrating myeloid cells might play a crucial role for limited efficacy of anti‐angiogenic therapy bypassing VEGF‐mediated pathways through expression of alternative proangiogenic factors. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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confidence: 99%

Microglia/macrophages express alternative proangiogenic factors depending on granulocyte content in human glioblastoma

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Kremenetskaia

Urbantat

et al. 2020

The Journal of Pathology

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“…These cells, through the release of CXCL2 in the microenvironment, participate in the building and stabilization of new tumor vessels. In fact, depleting the tumor of microglia or blocking CXCR2 on endothelial cells, significantly reduced glioma volume [ 72 , 73 ]. Likewise, CXCL1 and CXCL5 are interactors of CXCR2.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity Matters: Different Regions of Glioblastoma Are Characterized by Distinctive Tumor-Supporting Pathways

Manini

Caponnetto

Dalla

et al. 2020

Cancers

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The glioblastoma microenvironment plays a substantial role in glioma biology. However, few studies have investigated its spatial heterogeneity. Exploiting 5-ALA Fluorescence Guided Surgery (FGS), we were able to distinguish between the tumor core (ALA+), infiltrating area (ALA-PALE) and healthy tissue (ALA−) of the glioblastoma, based on the level of accumulated fluorescence. The aim of this study was to investigate the properties of the microenvironments associated with these regions. For this purpose, we isolated glioma-associated stem cells (GASC), resident in the glioma microenvironment, from ALA+, ALA-PALE and ALA− samples and compared them in terms of growth kinetic, phenotype and for the expression of 84 genes associated with cancer inflammation and immunity. Differentially expressed genes were correlated with transcriptomic datasets from TCGA/GTEX. Our results show that GASC derived from the three distinct regions, despite a similar phenotype, were characterized by different transcriptomic profiles. Moreover, we identified a GASC-based genetic signature predictive of overall survival and disease-free survival. This signature, highly expressed in ALA+ GASC, was also well represented in ALA PALE GASC. 5-ALA FGS allowed to underline the heterogeneity of the glioma microenvironments. Deepening knowledge of these differences can contribute to develop new adjuvant therapies targeting the crosstalk between tumor and its supporting microenvironment.

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“…In recent years, CXCR2 has been involved in the tumorigenesis, development and treatment of a variety of tumors, and the effect of the CXCR2 axis on the tumor microenvironment has received more and more attention. 41 For instance, CXCR2 activated by IL-8 promotes ovarian cancer EMT via Wnt/β-catenin pathway. 42 In addition, CXCR2 is also found to be regulated by miRNA.…”

Section: Discussionmentioning

confidence: 99%

Circ_0000215 Increases the Expression of CXCR2 and Promoted the Progression of Glioma Cells by Sponging miR-495-3p

Mutalifu

Zhang

et al. 2020

Technol Cancer Res Treat

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Background: In recent years, accumulating studies have found that circular RNA (circRNA) exerts a great effect on tumor progression. Circ_0000215, a novel circRNA, remains largely unknown in terms of its effect and mechanism in glioma. Method: Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to detect the expressions of circ_0000215, miR-495-3p and CXCR2 in human glial cell line HEB and glioma cell lines (A172, U251, U87, SHG-44, LN-18), human glioma tissues and adjacent healthy tissues. Gain- and loss-assays of circ_0000215 were conducted. Cell proliferation ability was detected via the CCK8 assay, and cell invasion ability was examined by Transwell assay. CXCR2 expression was evaluated via RT-PCR and Western blot. Moreover, bioinformatics was applied to analyze the targeting molecules of circ_0000215 and CXCR2. Verification of the relationship between these molecules were supported through the dual-luciferase reporter gene and RNA immunocoprecipitation (RIP) assay. Results: Circ_0000215 and CXCR2 were remarkably upregulated in glioma tissues and cells. Overexpression of circ_0000215 notably promoted the proliferation, invasion and epithelial-mesenchymal transition (EMT) but inhibited apoptosis of glioma cells, while knocking down circ_0000215 had the opposite effects. Additionally, miR-495-3p, a sponge RNA of circ_0000215, inhibited the growth, invasion and EMT of glioma cells. Mechanistically, miR-495-3p targeted CXCR2 and negatively regulated CXCR2/PI3K/Akt pathway. However, the effects of miR-495-3p were all dampened by overexpression of circ_0000215. Conclusion: These data demonstrated that circ_0000215 functions as a competitive endogenous RNA by sponging miR-495-3p, thus accelerating glioma progression through CXCR2 axis.

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The CXCR2/CXCL2 signalling pathway – An alternative therapeutic approach in high-grade glioma

Cited by 35 publications

References 34 publications

Microglia/macrophages express alternative proangiogenic factors depending on granulocyte content in human glioblastoma

Microglia/macrophages express alternative proangiogenic factors depending on granulocyte content in human glioblastoma

Heterogeneity Matters: Different Regions of Glioblastoma Are Characterized by Distinctive Tumor-Supporting Pathways

Circ_0000215 Increases the Expression of CXCR2 and Promoted the Progression of Glioma Cells by Sponging miR-495-3p

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