Microglial Cytokines Induce Invasiveness and Proliferation of Human Glioblastoma through Pyk2 and FAK Activation.
Microglial Cytokines Induce Invasiveness and Proliferation of Human Glioblastoma through Pyk2 and FAK Activation.
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DOI：
10.3390/cancers13246160
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发表时间：
2021-12-07
期刊：
影响因子：
5.2
通讯作者：
Kucheryavykh L
中科院分区：
文献类型：
--
作者：
Nuñez RE;Del Valle MM;Ortiz K;Almodovar L;Kucheryavykh L
小胶质细胞浸润大多数胶质瘤，并已被证明促进肿瘤生长、侵袭和治疗抵抗。为了开发更好的治疗方法，考虑到小胶质细胞在肿瘤进展中的支持作用，胶质瘤-小胶质细胞相互作用的功能和机制途径需要被识别和实验解剖。我们最近的研究和文献报道揭示了Pyk2和FAK在胶质母细胞瘤中的过表达。Pyk2和FAK信号通路已被证明调节胶质瘤细胞的迁移和增殖，包括小胶质细胞促进胶质瘤细胞迁移。然而，小胶质细胞释放的调节Pyk2和FAK促进胶质瘤侵袭和增殖的特定因子尚不清楚。本研究的目的是鉴定诱导Pyk2-和fak依赖性胶质瘤细胞增殖和侵袭性激活的关键小胶质细胞来源的信号分子。胶质母细胞瘤是成人中最具侵袭性的脑肿瘤。多种证据表明，小胶质细胞创造了一个有利于胶质瘤侵袭和增殖的微环境。我们之前的研究和文献报道表明，局灶黏附激酶（FAK）和富含脯氨酸的酪氨酸激酶2 （Pyk2）参与肿瘤浸润性小胶质细胞刺激的胶质瘤细胞增殖和侵袭。然而，在胶质瘤细胞中调节Pyk2和FAK信号的特定小胶质细胞释放因子尚不清楚。本研究采用RT-PCR和western blotting对20例人胶质母细胞瘤标本进行了评价。Pierson相关试验表明，肿瘤纯化小胶质细胞中血小板衍生生长因子β(PDGFβ)、基质衍生因子1α (SDF-1α)、IL-6、IL-8和表皮生长因子（EGF）的基因表达水平与胶质瘤细胞中p-Pyk2 （Y579/Y580）和p-FAK（Y925）的水平之间存在0.6-1.0的相关性。siRNA对三种原代胶质母细胞瘤细胞系Pyk2或FAK的敲除，与细胞因子受体抑制剂吉非替尼（1 μM）、DMPQ （200 nM）和burixafor （1 μM）联合，鉴定出EGF、PDGFβ和SDF-1α是Pyk2和FAK依赖性的侵袭样体形成和胶质瘤细胞迁移激活的关键细胞外因子。EGF和IL-6被确定为Pyk2和fak依赖性细胞活力和有丝分裂激活的调节因子。
Microglia infiltrate most gliomas and have been demonstrated to promote tumor growth, invasion, and treatment resistance. To develop improved treatment methods, that take into consideration the supporting role of microglia in tumor progression, the functional and mechanistic pathways of glioma–microglia interactions need to be identified and experimentally dissected. Our recent studies and literature reports revealed the overexpression of Pyk2 and FAK in glioblastomas. Pyk2 and FAK signaling pathways have been shown to regulate migration and proliferation in glioma cells, including microglia-promoted glioma cell migration. However, the specific factors released by microglia that modulate Pyk2 and FAK to promote glioma invasiveness and proliferation are poorly understood. The aim of this study was to identify key microglia-derived signaling molecules that induce the activation of Pyk2- and FAK-dependent glioma cell proliferation and invasiveness. Glioblastoma is the most aggressive brain tumor in adults. Multiple lines of evidence suggest that microglia create a microenvironment favoring glioma invasion and proliferation. Our previous studies and literature reports indicated the involvement of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) in glioma cell proliferation and invasion, stimulated by tumor-infiltrating microglia. However, the specific microglia-released factors that modulate Pyk2 and FAK signaling in glioma cells are unknown. In this study, 20 human glioblastoma specimens were evaluated with the use of RT-PCR and western blotting. A Pierson correlation test demonstrated a correlation (0.6–1.0) between the gene expression levels for platelet-derived growth factor β(PDGFβ), stromal-derived factor 1α (SDF-1α), IL-6, IL-8, and epidermal growth factor (EGF) in tumor-purified microglia and levels of p-Pyk2 (Y579/Y580) and p-FAK(Y925) in glioma cells. siRNA knockdown against Pyk2 or FAK in three primary glioblastoma cell lines, developed from the investigated specimens, in combination with the cytokine receptor inhibitors gefitinib (1 μM), DMPQ (200 nM), and burixafor (1 μM) identified EGF, PDGFβ, and SDF-1α as key extracellular factors in the Pyk2- and FAK-dependent activation of invadopodia formation and the migration of glioma cells. EGF and IL-6 were identified as regulators of the Pyk2- and FAK-dependent activation of cell viability and mitosis.
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影响因子：
4.1
作者：
Kirshner ZZ;Gibbs RB
通讯作者：
Gibbs RB
影响因子：
3.3
作者：
Carvalho da Fonseca, Anna Carolina;Wang, Huaqing;Fan, Haitao;Chen, Xuebo;Zhang, Ian;Zhang, Leying;Lima, Flavia Regina Souza;Badie, Behnam
通讯作者：
Badie, Behnam
影响因子：
3.3
作者：
Deramaudt TB;Dujardin D;Hamadi A;Noulet F;Kolli K;De Mey J;Takeda K;Rondé P
通讯作者：
Rondé P
影响因子：
8
作者：
Hecker, TP;Ding, Q;Gladson, CL
通讯作者：
Gladson, CL
影响因子：
5.7
作者：
Coniglio, Salvatore J.;Eugenin, Eliseo;Segall, Jeffrey E.
通讯作者：
Segall, Jeffrey E.