Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden.
Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden; Swedish University of Agricultural Sciences, Department of Biomedical Sciences and Veterinary Public Health, Box 7028, SE-750 07 Uppsala, Sweden.
Cell Signal. 2017 Sep;37:81-92. doi: 10.1016/j.cellsig.2017.06.004. Epub 2017 Jun 6.
Glioblastoma (GBM) heterogeneity is the main obstacle to efficient treatment due to the existence of subpopulation of cells with increased tumorigenicity and network of tumor associated parenchymal cells in the tumor microenvironment. We previously demonstrated that mast cells (MCs) infiltrate mouse and human gliomas in response to variety of signals in a glioma grade-dependent manner. However, the role of MCs in glioma development and the mechanisms behind MCs-glioma cells interaction remain unidentified. In the present study, we show that MCs upon activation by glioma cells produce soluble factors including IL-6, which are documented to be involved in cancer-related activities. We observe 'tumor educated' MCs decrease glioma cell proliferation and migration, reduce self-renewal capacity and expression of stemness markers but in turn promote glioma cell differentiation. 'Tumor educated' MC derived mediators exert these effects via inactivation of STAT3 signaling pathway through GSK3β down-regulation. We identified 'tumor educated' MC derived IL-6 as one of the contributors among the complex mixture of MCs mediators, to be partially involved in the observed MC induced biological effect on glioma cells. Thus, MC mediated abolition of STAT3 signaling hampers glioma cell proliferation and migration by suppressing their stemness and inducing differentiation via down-regulation of GSK3β expression. Targeting newly identified inflammatory MC-STAT3 axis could contribute to patient tailored therapy and unveil potential future therapeutic opportunities for patients.
胶质母细胞瘤（GBM）异质性是有效治疗的主要障碍，这是由于肿瘤微环境中存在具有更高肿瘤形成能力的细胞亚群和与肿瘤相关的实质细胞网络。我们之前的研究表明，肥大细胞（MCs）会响应胶质瘤中的各种信号，以胶质瘤分级依赖的方式浸润到小鼠和人类的胶质瘤中。然而，MCs 在胶质瘤发生发展中的作用以及 MCs-胶质瘤细胞相互作用的机制仍不清楚。在本研究中，我们发现，MCs 在被胶质瘤细胞激活后会产生包括 IL-6 在内的可溶性因子，这些因子被证实参与了与癌症相关的活动。我们观察到“肿瘤教育”的 MCs 会降低胶质瘤细胞的增殖和迁移，降低自我更新能力和干性标志物的表达，但会促进胶质瘤细胞的分化。“肿瘤教育”的 MC 衍生的介质通过下调 GSK3β 来抑制 STAT3 信号通路，从而发挥这些作用。我们确定了“肿瘤教育”的 MC 衍生的 IL-6 是 MC 介质复杂混合物中的一个贡献者，它部分参与了观察到的 MC 对胶质瘤细胞的诱导生物学效应。因此，MC 介导的 STAT3 信号抑制通过下调 GSK3β 的表达来抑制其干性并诱导分化，从而阻碍了胶质瘤细胞的增殖和迁移。靶向新鉴定的炎症性 MC-STAT3 轴可能有助于为患者量身定制治疗方案，并为患者提供潜在的未来治疗机会。
