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The CXCR2/CXCL2 signalling pathway - An alternative therapeutic approach in high-grade glioma.
European Journal of Cancer ( IF 8.4 ) Pub Date : 2020-01-09 , DOI: 10.1016/j.ejca.2019.12.005
Güliz Acker 1 , Julia Zollfrank 2 , Claudius Jelgersma 2 , Melina Nieminen-Kelhä 2 , Irina Kremenetskaia 2 , Susanne Mueller 3 , Adnan Ghori 2 , Peter Vajkoczy 2 , Susan Brandenburg 2
Affiliation  

OBJECTIVE Besides VEGF, alternative signalling via CXCR2 and its ligands CXCL2/CXCL8 is a crucial part of angiogenesis in glioblastoma. Our aim was to understand the role of CXCR2 for glioma biology and elucidate the therapeutic potential of its specific inhibition. METHODS GL261 glioma cells were implanted intracranially in syngeneic mice. The 14 or 7 days of local or systemic treatment with CXCR2-antagonist (SB225002) was initiated early on the day of tumour cell implantation or delayed after 14 days of tumour growth. Glioma volume was verified using MRI before and after treatment. Immunofluorescence staining was used to investigate tumour progression, angiogenesis and microglial behaviour. Furthermore, in vitro assays and gene expression analyses of glioma and endothelial cells were performed to validate inhibitor activity. RESULTS CXCR2-blocking led to significantly reduced glioma volumes of around 50% after early and delayed local treatments. The treated tumours were comparable with controls regarding invasiveness, proliferation and apoptotic cell activity. Furthermore, no differences in CXCR2/CXCL2 expression were observed. However, immunostaining revealed reduction in vessel density and accumulation of microglia/macrophages, whereas interaction of these myeloid cells with tumour vessels was enhanced. In vitro analyses of the CXCR2-antagonist showed its direct impact on proliferation of glioma and endothelial cells if used at higher concentrations. In addition, expression of CXCR2/CXCL2 signalling genes was increased in both cell types by SB225002, but VEGF-relevant genes were unaffected. CONCLUSION The CXCR2-antagonist inhibited glioma growth during tumour initiation and progression, whereas treatment was well-tolerated by the recipients. Thus, the CXCR2/CXCL2 signalling represents a promising therapeutic target in glioma.

中文翻译:

CXCR2 / CXCL2信号通路-高度神经胶质瘤的另一种治疗方法。

目的除了VEGF,经由CXCR2及其配体CXCL2 / CXCL8的替代信号传导是胶质母细胞瘤血管生成的关键部分。我们的目的是了解CXCR2在神经胶质瘤生物学中的作用,并阐明其特异性抑制作用的治疗潜力。方法将GL261神经胶质瘤细胞颅内植入同基因小鼠体内。用CXCR2拮抗剂(SB225002)进行14或7天的局部或全身治疗是在肿瘤细胞植入当天开始或在肿瘤生长14天之后推迟。治疗前后使用MRI核实神经胶质瘤的体积。免疫荧光染色用于研究肿瘤的进展,血管生成和小胶质细胞的行为。此外,进行了胶质瘤和内皮细胞的体外测定和基因表达分析,以验证抑制剂的活性。结果在早期和延迟的局部治疗后,CXCR2阻滞导致胶质瘤体积显着减少约50%。在侵袭性,增殖和凋亡细胞活性方面,治疗的肿瘤与对照组相当。此外,未观察到CXCR2 / CXCL2表达的差异。然而,免疫染色显示血管密度的降低和小胶质细胞/巨噬细胞的积累,而这些髓样细胞与肿瘤血管的相互作用得到增强。CXCR2拮抗剂的体外分析表明,如果以更高的浓度使用,它对神经胶质瘤和内皮细胞的增殖具有直接影响。此外,SB225002在两种细胞类型中均增加了CXCR2 / CXCL2信号转导基因的表达,但与VEGF相关的基因并未受到影响。结论CXCR2拮抗剂在肿瘤的发生和发展过程中抑制神经胶质瘤的生长,而接受者对治疗的耐受性很好。因此,CXCR2 / CXCL2信号代表神经胶质瘤中有希望的治疗靶点。
更新日期:2020-01-11
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