Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panamá, Panamá.
Neuro Oncol. 2018 Apr 9;20(5):621-631. doi: 10.1093/neuonc/noy008.
Glioblastoma (GBM) is one of the most aggressive human brain tumors, with a median survival of 15-18 months. There is a desperate need to find novel therapeutic targets. Various receptor protein kinases have been identified as potential targets; however, response rates in clinical studies have been somewhat disappointing. Targeting the spleen tyrosine kinase (SYK), which acts downstream of a range of oncogenic receptors, may therefore show more promising results.
Kinase expression of brain tumor samples including GBM and low-grade tumors were compared with normal brain and normal human astrocytes by microarray analysis. Furthermore, SYK, LYN, SLP76, and PLCG2 protein expressions were analyzed by immunohistochemistry, western blot, and immunofluorescence of additional GBM patient samples, murine glioma samples, and cell lines. SYK was then blocked chemically and genetically in vitro and in vivo in 2 different mouse models. Multiphoton intravital imaging and multicolor flow cytometry were performed in a syngeneic immunocompetent C57BL/6J mouse GL261 glioma model to study the effect of these inhibitors on the tumor microenvironment.
SYK, LYN, SLP76, and PLCG2 were found expressed in human and murine glioma samples and cell lines. SYK inhibition blocked proliferation, migration, and colony formation. Flow cytometric and multiphoton imaging imply that targeting SYK in vivo attenuated GBM tumor growth and invasiveness and reduced B and CD11b+ cell mobility and infiltration.
Our data suggest that gliomas express a SYK signaling network important in glioma progression, inhibition of which results in reduced invasion with slower tumor progression.
胶质母细胞瘤（GBM）是最具侵袭性的人类脑肿瘤之一，中位生存期为 15-18 个月。因此迫切需要寻找新的治疗靶点。各种受体蛋白激酶已被确定为潜在的靶点；然而，临床研究中的反应率有些令人失望。针对脾酪氨酸激酶（SYK）可能会显示出更有前景的结果，SYK 作为一系列致癌受体的下游分子发挥作用。
通过微阵列分析比较了包括 GBM 和低级别肿瘤在内的脑肿瘤样本与正常大脑和正常人类星形胶质细胞的激酶表达。此外，通过免疫组织化学、western blot 和另外的 GBM 患者样本、鼠胶质瘤样本和细胞系的免疫荧光分析，分析了 SYK、LYN、SLP76 和 PLCG2 蛋白的表达。然后在体外和体内通过化学和遗传方法阻断 SYK，在两种不同的小鼠模型中进行。在同种异体免疫活性 C57BL/6J 小鼠 GL261 胶质母细胞瘤模型中进行多光子活体成像和多色流式细胞术，以研究这些抑制剂对肿瘤微环境的影响。
在人类和鼠胶质瘤样本和细胞系中发现了 SYK、LYN、SLP76 和 PLCG2 的表达。SYK 抑制阻断了增殖、迁移和集落形成。流式细胞术和多光子成像表明，体内靶向 SYK 可减弱 GBM 肿瘤生长和侵袭，并降低 B 和 CD11b+细胞的迁移和浸润。
我们的数据表明，神经胶质瘤表达了一个在神经胶质瘤进展中重要的 SYK 信号网络，抑制该信号网络可减少侵袭，减缓肿瘤进展。
