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Published on: February 20, 2018
Expression of the new CXCL12 receptor, CXCR7, in gliomas
Chiara Calatozzolo1, Alessandra Canazza, Bianca Pollo
1Neuropathology Unit, Istituto Nazionale Neurologico Carlo Besta, Milan, Italy.
Abstract:
Gliomas are very invasive brain tumors with poor prognosis and therefore any attempt to limit tumor cell dissemination in the brain is expected to improve glioma treatment. The recent deorphanization of CXCR7 as additional receptor for CXCL12 and CXCL11 has raised key issues on its interaction with the CXCL12/CXCR4 axis as a mechanism to modulate glioma cell migration. In this work we investigated protein and mRNA expression of the two chemokines CXCL12 and CXCL11, together with their receptors CXCR4 and CXCR7 in human glioma specimens and cell lines by immunohistochemistry, flow cytometry and quantitative real-time PCR. The main purpose of this study was to find out whether and at what extent CXCR4 and CXCR7 are differentially expressed in glioma cells. In human glioma specimens the levels of CXCL11 and CXCR4 mRNA were significantly higher in glioblastomas compared to non-tumor controls or low grade gliomas, whilst no difference was found for CXCL12 and CXCR7 mRNA expression. In cell lines, flow cytometry and immunocytochemical experiments showed CXCR4 was mainly expressed irrespective of its membrane or intracellular localization. In contrast, a predominant intracellular localization together with a negligible membrane expression of CXCR7 was found in all cells examined. In in vitro experiments CXCR4 and CXCR7 antagonists and the silencing of CXCR4 showed complete inhibition of glioma proliferation. Our findings, in agreement with previous data, suggest that in human glioma cells the prevalent intracellular localization of CXCR7 might modulate the functionality of CXCL11/12 either acting as a scavenger for these chemokines or interfering with the signaling pathways activated by the stimulation of CXCR4.
Insights
This study reveals that glioma cells express CXCR4 and CXCR7 receptors. Inhibiting these receptors stopped glioma cell proliferation, suggesting new therapeutic targets for brain tumors.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cell Signaling
Background:
- Gliomas are aggressive brain tumors with poor outcomes, necessitating strategies to inhibit tumor cell spread.
- The CXCL12/CXCR4 axis is implicated in glioma cell migration, with CXCR7 recently identified as an additional receptor for CXCL12 and CXCL11.
Purpose of the Study:
- To investigate the differential expression of CXCR4 and CXCR7 in human glioma specimens and cell lines.
- To explore the functional roles of these chemokine receptors in glioma cell proliferation and migration.
Main Methods:
- Immunohistochemistry, flow cytometry, and quantitative real-time PCR were used to assess protein and mRNA expression of CXCL12, CXCL11, CXCR4, and CXCR7.
- In vitro experiments utilized CXCR4 and CXCR7 antagonists and CXCR4 silencing to evaluate effects on glioma proliferation.
Main Results:
- CXCL11 and CXCR4 mRNA levels were significantly elevated in glioblastomas compared to non-tumor controls and low-grade gliomas.
- Glioma cell lines predominantly expressed CXCR4 intracellularly and CXCR7 intracellularly with minimal membrane presence.
- Inhibition of CXCR4 and CXCR7, or silencing of CXCR4, completely inhibited glioma cell proliferation in vitro.
Conclusions:
- The differential expression and predominantly intracellular localization of CXCR7 in glioma cells suggest it may modulate CXCL11/12 functionality.
- CXCR7 might act as a scavenger for CXCL11/12 or interfere with CXCR4 signaling pathways, impacting glioma progression.
- Targeting the CXCR4/CXCR7 axis presents a promising therapeutic strategy for improving glioma treatment outcomes.
