Wang Ying, Liu Tao, Yang Ning, Xu Shuo, Li Xingang, Wang Donghai
Department of Rehabilitation, Qilu Children's Hospital of Shandong University, Jinan, Shandong, P.R. China.
Department of Neurosurgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China.
Oncol Rep. 2016 Dec;36(6):3522-3528. doi: 10.3892/or.2016.5171. Epub 2016 Oct 13.
Glioblastoma (GBM) is a highly malignant brain tumor characterized by invasion tendency. Macrophage infiltration is associated with GBM invasion, but the mechanisms remain unclear. Hypoxia is an outstanding characteristic of GBM tissue. Hypoxia microenvironment modulates the biological behaviors of both tumor cells and infiltrated immune cells, including macrophages. In the present study, we analyzed the effects of hypoxia and macrophages on invasion of GBM cells and its potential mechanisms. We found that both hypoxia and macrophage supernatant promoted GBM cells invasion and matrix metalloproteinase (MMP)-9 expression, and hypoxia modulated the invasive activity of GBM cells by upregulating their CCR5 expression. The supernatant of hypoxic macrophages also showed greater pro-invasion effect than normoxic macrophages through the elevated secretion of CCL4. Moreover, we found that interferon regulatory factor-8 (IRF-8) was possibly involved in hypoxia-modulated CCL4 expression of macrophages. Taken together, the present study found that macrophages promoted GBM invasion by the CCL4-CCR5 axis, and hypoxia enhanced the interaction between these two types of cells by upregulating both CCL4 and CCR5 expression, respectively. The results of the present study suggested that hypoxia would be a potential target for the development of immune therapies of GBM.
胶质母细胞瘤（GBM）是一种具有侵袭倾向的高度恶性脑肿瘤。巨噬细胞浸润与GBM侵袭相关，但其机制仍不清楚。缺氧是GBM组织的一个突出特征。缺氧微环境调节肿瘤细胞和浸润免疫细胞（包括巨噬细胞）的生物学行为。在本研究中，我们分析了缺氧和巨噬细胞对GBM细胞侵袭的影响及其潜在机制。我们发现缺氧和巨噬细胞上清液均促进GBM细胞侵袭和基质金属蛋白酶（MMP）-9表达，且缺氧通过上调GBM细胞的CCR5表达来调节其侵袭活性。缺氧巨噬细胞的上清液通过增加CCL4分泌也比常氧巨噬细胞表现出更强的促侵袭作用。此外，我们发现干扰素调节因子8（IRF-8）可能参与缺氧调节的巨噬细胞CCL4表达。综上所述 ，本研究发现巨噬细胞通过CCL4-CCR5轴促进GBM侵袭，而缺氧分别通过上调CCL4和CCR5表达增强这两种细胞之间的相互作用。本研究结果表明，缺氧将是GBM免疫治疗开发的一个潜在靶点。
