Center for Oncology and Cell Biology, Laboratory for Brain Tumor Biology, Feinstein Institute for Medical Research, 350 Community Dr, 11030, Manhasset, NY, USA.
Adv Exp Med Biol. 2020;1202:129-149. doi: 10.1007/978-3-030-30651-9_7.
Tumor cell invasiveness is a critical challenge in the clinical management of glioma patients. In addition, there is accumulating evidence that current therapeutic modalities, including anti-angiogenic therapy and radiotherapy, can enhance glioma invasiveness. Glioma cell invasion is stimulated by both autocrine and paracrine factors that act on a large array of cell surface-bound receptors. Key signaling elements that mediate receptor-initiated signaling in the regulation of glioblastoma invasion are Rho family GTPases, including Rac, RhoA and Cdc42. These GTPases regulate cell morphology and actin dynamics and stimulate cell squeezing through the narrow extracellular spaces that are typical of the brain parenchyma. Transient attachment of cells to the extracellular matrix is also necessary for glioblastoma cell invasion. Interactions with extracellular matrix components are mediated by integrins that initiate diverse intracellular signalling pathways. Key signaling elements stimulated by integrins include PI3K, Akt, mTOR and MAP kinases. In order to detach from the tumor mass, glioma cells secrete proteolytic enzymes that cleave cell surface adhesion molecules, including CD44 and L1. Key proteases produced by glioma cells include uPA, ADAMs and MMPs. Increased understanding of the molecular mechanisms that control glioma cell invasion has led to the identification of molecular targets for therapeutic intervention in this devastating disease.
肿瘤细胞的侵袭性是胶质母细胞瘤患者临床治疗的一个关键挑战。此外，越来越多的证据表明，目前的治疗方法，包括抗血管生成治疗和放疗，可以增强胶质瘤的侵袭性。胶质瘤细胞的侵袭受到自分泌和旁分泌因子的刺激，这些因子作用于大量细胞表面结合的受体。介导受体起始信号在调节胶质母细胞瘤侵袭中的关键信号元件是 Rho 家族 GTPases，包括 Rac、RhoA 和 Cdc42。这些 GTPases 调节细胞形态和肌动蛋白动力学，并通过大脑实质中典型的狭窄细胞外空间刺激细胞挤压。细胞与细胞外基质的短暂附着对于胶质母细胞瘤细胞的侵袭也是必要的。整合素介导细胞与细胞外基质成分的相互作用，启动各种细胞内信号通路。整合素刺激的关键信号元件包括 PI3K、Akt、mTOR 和 MAP 激酶。为了从肿瘤块中分离出来，胶质瘤细胞分泌蛋白水解酶，切割细胞表面粘附分子，包括 CD44 和 L1。胶质瘤细胞产生的关键蛋白酶包括 uPA、ADAMs 和 MMPs。对控制胶质瘤细胞侵袭的分子机制的深入了解，导致了在这种毁灭性疾病中治疗干预的分子靶点的确定。
