Shi Ping, Tian Jia, Ulm Brittany S, Mallinger Julianne C, Khoshbouei Habibeh, Deleyrolle Loic P, Sarkisian Matthew R
Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United States.
Department of Neurosurgery, University of Florida College of Medicine, Gainesville, FL, United States.
Front Oncol. 2022 Mar 11;12:837589. doi: 10.3389/fonc.2022.837589. eCollection 2022.
Tumor Treating Fields (TTFields) are low-intensity, alternating intermediate-frequency (200 kHz) electrical fields that extend survival of glioblastoma patients receiving maintenance temozolomide (TMZ) chemotherapy. How TTFields exert efficacy on cancer over normal cells or interact with TMZ is unclear. Primary cilia are microtubule-based organelles triggered by extracellular ligands, mechanical and electrical field stimulation and are capable of promoting cancer growth and TMZ chemoresistance. We found in both low- and high-grade patient glioma cell lines that TTFields ablated cilia within 24 h. Halting TTFields treatment led to recovered frequencies of elongated cilia. Cilia on normal primary astrocytes, neurons, and multiciliated/ependymal cells were less affected by TTFields. The TTFields-mediated loss of glioma cilia was partially rescued by chloroquine pretreatment, suggesting the effect is in part due to autophagy activation. We also observed death of ciliated cells during TTFields by live imaging. Notably, TMZ and TTFields have opposing effects on glioma ciliogenesis. TMZ-induced stimulation of ciliogenesis in both adherent cells and gliomaspheres was blocked by TTFields. Surprisingly, the inhibitory effects of TTFields and TMZ on tumor cell recurrence are linked to the relative timing of TMZ exposure to TTFields and ARL13B cilia. Finally, TTFields disrupted cilia in patient tumors treated . Our findings suggest that the efficacy of TTFields may depend on the degree of tumor ciliogenesis and relative timing of TMZ treatment.
肿瘤治疗电场（TTFields）是一种低强度、交替的中频（200kHz）电场，可延长接受替莫唑胺（TMZ）维持化疗的胶质母细胞瘤患者的生存期。目前尚不清楚TTFields如何对癌细胞而非正常细胞发挥作用，以及它如何与TMZ相互作用。原发性纤毛是以微管为基础的细胞器，可由细胞外配体、机械和电场刺激触发，能够促进癌症生长和TMZ化疗耐药。我们在低级别和高级别患者的胶质瘤细胞系中均发现，TTFields可在24小时内使纤毛消融。停止TTFields治疗后，纤毛伸长频率恢复。正常原代星形胶质细胞、神经元以及多纤毛/室管膜细胞上的纤毛受TTFields的影响较小。氯喹预处理可部分挽救TTFields介导的胶质瘤纤毛缺失，这表明该效应部分归因于自噬激活。我们还通过实时成像观察到TTFields作用期间纤毛细胞的死亡。值得注意的是，TMZ和TTFields对胶质瘤纤毛发生具有相反的作用。TTFields可阻断TMZ诱导的贴壁细胞和胶质瘤球中的纤毛发生。令人惊讶的是，TTFields和TMZ对肿瘤细胞复发的抑制作用与TMZ暴露于TTFields和ARL13B纤毛的相对时间有关。最后，TTFields破坏了接受治疗的患者肿瘤中的纤毛。我们的研究结果表明，TTFields的疗效可能取决于肿瘤纤毛发生的程度以及TMZ治疗的相对时间。
