Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
Max Delbruck Center, Molecular Neurosciences, Berlin-Buch, Germany.
Br J Cancer. 2020 Aug;123(3):438-448. doi: 10.1038/s41416-020-0862-2. Epub 2020 May 11.
Malignant tumours release factors, which attract myeloid cells and induce their polarisation to pro-invasive, immunosuppressive phenotypes. Brain-resident microglia and peripheral macrophages accumulate in the tumour microenvironment of glioblastoma (GBM) and induce immunosuppression fostering tumour progression. Macrophage colony stimulating factors (CSFs) control the recruitment of myeloid cells during peripheral cancer progression, but it is disputable, which CSFs drive their accumulation in gliomas.
The expression of CSF2 (encoding granulocyte-macrophage colony stimulating factor) was determined in TCGA datasets and five human glioma cell lines. Effects of stable CSF2 knockdown in glioma cells or neutralising CSF2 or receptor CSF2Rα antibodies on glioma invasion were tested in vitro and in vivo.
CSF2 knockdown or blockade of its signalling reduced microglia-dependent glioma invasion in microglia-glioma co-cultures. CSF2-deficient human glioma cells encapsulated in cell-impermeable hollow fibres and transplanted to mouse brains, failed to attract microglia, but stimulated astrocyte recruitment. CSF2-depleted gliomas were smaller, attracted less microglia and macrophages, and provided survival benefit in tumour-bearing mice. Apoptotic microglia/macrophages were detected in CSF2-depleted tumours.
CSF2 is overexpressed in a subset of mesenchymal GBMs in association with high immune gene expression. Tumour-derived CSF2 attracts, supports survival and induces pro-tumorigenic polarisation of microglia and macrophages.
恶性肿瘤释放的因子会吸引髓系细胞，并诱导其向促侵袭、免疫抑制表型极化。脑内小胶质细胞和外周巨噬细胞在胶质母细胞瘤（GBM）的肿瘤微环境中积聚，并诱导免疫抑制，促进肿瘤进展。巨噬细胞集落刺激因子（CSFs）控制着外周癌细胞进展过程中髓系细胞的募集，但哪种 CSF 驱动其在神经胶质瘤中的积累仍存在争议。
在 TCGA 数据集和 5 个人类神经胶质瘤细胞系中测定 CSF2（编码粒细胞-巨噬细胞集落刺激因子）的表达。在体外和体内测试稳定敲低神经胶质瘤细胞中的 CSF2 或中和 CSF2 或受体 CSF2Rα 抗体对神经胶质瘤侵袭的影响。
CSF2 敲低或阻断其信号通路可减少小胶质细胞依赖性神经胶质瘤在小胶质细胞-神经胶质瘤共培养物中的侵袭。包封在细胞不可渗透的中空纤维中的 CSF2 缺陷型人神经胶质瘤细胞移植到小鼠大脑中，无法吸引小胶质细胞，但刺激星形胶质细胞募集。CSF2 耗竭的神经胶质瘤体积较小，吸引的小胶质细胞和巨噬细胞较少，并为荷瘤小鼠提供生存获益。在 CSF2 耗竭的肿瘤中检测到凋亡的小胶质细胞/巨噬细胞。
CSF2 在与高免疫基因表达相关的间充质 GBM 的亚群中过度表达。肿瘤衍生的 CSF2 吸引、支持存活并诱导小胶质细胞和巨噬细胞的促肿瘤发生极化。
