Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
Dompé Farmaceutici SpA, L'Aquila, Italy.
Aging (Albany NY). 2020 Jan 27;12(2):1928-1951. doi: 10.18632/aging.102733.
Glioblastoma (GB) is the most representative form of primary malignant brain tumour. Several studies indicated a pleiotropic role of CXCL8 in cancer due to its ability to modulate the tumour microenvironment, growth and aggressiveness of tumour cell. Previous studies indicated that CXCL8 by its receptors (CXCR1 and CXCR2) induced activation of the PI3K/p-Akt pathway, a crucial event in the regulation of cytoskeleton rearrangement and cell mobilization. Human GB primary cell culture and U-87MG cell line were used to study the effects of CXCR1 and CXCR2 blockage, by a dual allosteric antagonist, on cell migration and cytoskeletal dynamics. The data obtained point towards a specific effect of autocrine CXCL8 signalling on GB cell invasiveness by the activation of pathways involved in cell migration and cytoskeletal dynamics, such as PI3K/p-Akt/p-FAK, p-cortactin, RhoA, Cdc42, Acetylated α-tubulin and MMP2. All the data obtained support the concept that autocrine CXCL8 signalling plays a key role in the activation of an aggressive phenotype in primary glioblastoma cells and U-87MG cell line. These results provide new insights about the potential of a pharmacological approach targeting CXCR1/CXCR2 pathways to decrease migration and invasion of GB cells in the brain parenchyma, one of the principal mechanisms of recurrence.
胶质母细胞瘤（GB）是原发性恶性脑肿瘤中最具代表性的形式。由于其能够调节肿瘤微环境、肿瘤细胞的生长和侵袭性，因此有几项研究表明 CXCL8 在癌症中具有多效性作用。先前的研究表明，CXCL8 通过其受体（CXCR1 和 CXCR2）诱导 PI3K/p-Akt 通路的激活，这是调节细胞骨架重排和细胞迁移的关键事件。用人 GB 原代细胞培养物和 U-87MG 细胞系研究了双重变构拮抗剂对细胞迁移和细胞骨架动力学的 CXCR1 和 CXCR2 阻断的影响。获得的数据表明，自分泌 CXCL8 信号通过激活参与细胞迁移和细胞骨架动力学的途径（如 PI3K/p-Akt/p-FAK、p-cortactin、RhoA、Cdc42、乙酰化 α-微管蛋白和 MMP2）对 GB 细胞侵袭具有特异性作用。所有获得的数据均支持自分泌 CXCL8 信号在原发性神经胶质瘤细胞和 U-87MG 细胞系中激活侵袭表型中发挥关键作用的概念。这些结果为靶向 CXCR1/CXCR2 途径的药理学方法提供了新的见解，以减少脑实质中 GB 细胞的迁移和侵袭，这是复发的主要机制之一。
