Paulo Niemeyer State Brain Institute (IECPN), Rio de Janeiro, Brazil.
Department of Anatomy, University of Kiel, Kiel, Germany.
Glia. 2018 Aug;66(8):1542-1565. doi: 10.1002/glia.23309. Epub 2018 Feb 21.
An outstanding characteristic of gliomas is their infiltration into brain parenchyma, a property that impairs complete surgical resection; consequently, these tumors might recur, resulting in a high mortality rate. Gliomas invade along preferential routes, such as those along white matter tracts and in the perineuronal and perivascular spaces. Brain extracellular components and their partners and modulators play a crucial role in glioma cell invasion. This review presents an extensive survey of the literature, showing how the brain extracellular matrix (ECM) is modulated during the glioma infiltration process. We explore aspects of ECM interaction with glioma cells, reviewing the main glycosaminoglycans, glycoproteins and proteoglycans. We discuss the roles of ECM-binding proteins, including CD44, RHAMM, integrins and axonal guidance molecules, and highlight the role of proteases and glycosidases in glioma infiltration; in binding and release chemokines, cytokines and growth factors; and in generating new bioactive ECM fragments. We also consider the roles of cytoskeletal signaling, angiogenesis, miRNAs and the glial-to-mesenchymal transition linked to glioma invasion. We closely discuss therapeutic approaches based on the modulation of the extracellular matrix, targeting the control of glioma infiltration, its relative failure in clinical trials, and potential means to overcome this difficulty.
神经胶质瘤的一个显著特征是其对脑实质的浸润,这一特性会妨碍完全的手术切除;因此,这些肿瘤可能会复发,导致高死亡率。神经胶质瘤沿着白质束和神经周隙及血管周隙等优先途径浸润。脑细胞外基质及其配体和调节剂在神经胶质瘤细胞浸润中起着至关重要的作用。这篇综述广泛查阅了文献,展示了脑细胞外基质在神经胶质瘤浸润过程中是如何被调节的。我们探讨了 ECM 与神经胶质瘤细胞相互作用的几个方面,回顾了主要的糖胺聚糖、糖蛋白和蛋白聚糖。我们讨论了 ECM 结合蛋白的作用,包括 CD44、RHAMM、整合素和轴突导向分子,并强调了蛋白酶和糖苷酶在神经胶质瘤浸润中的作用;在结合和释放趋化因子、细胞因子和生长因子;以及产生新的生物活性 ECM 片段。我们还考虑了与神经胶质瘤浸润相关的细胞骨架信号转导、血管生成、miRNA 和神经胶质向间充质转化的作用。我们还详细讨论了基于细胞外基质调节的治疗方法,这些方法针对控制神经胶质瘤浸润,以及其在临床试验中的相对失败,以及克服这一困难的潜在手段。