Schlieper-Scherf Steffen, Hebach Nils, Hausmann David, Azorín Daniel D, Hoffmann Dirk C, Horschitz Sandra, Maier Elena, Koch Phillip, Karreman Matthia A, Etminan Nima, Ratliff Miriam
Department of Neurosurgery, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.
Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
J Neurooncol. 2024 Oct;170(1):139-151. doi: 10.1007/s11060-024-04786-0. Epub 2024 Aug 1.
This study investigates the biological effect of Tumor Treating Fields (TTFields) on key drivers of glioblastoma's malignancy-tumor microtube (TM) formation-and on the function and overall integrity of the tumor cell network.
Using a two-dimensional monoculture GB cell network model (2DTM) of primary glioblastoma cell (GBC) cultures (S24, BG5 or T269), we evaluated the effects of TTFields on cell density, interconnectivity and structural integrity of the tumor network. We also analyzed calcium (Ca) transient dynamics and network morphology, validating findings in patient-derived tumoroids and brain tumor organoids.
In the 2DTM assay, TTFields reduced cell density by 85-88% and disrupted network interconnectivity, particularly in cells with multiple TMs. A "crooked TM" phenotype emerged in 5-6% of treated cells, rarely seen in controls. Ca transients were significantly compromised, with global Ca activity reduced by 51-83%, active and periodic cells by over 50%, and intercellular co-activity by 52% in S24, and almost completely in BG5 GBCs. The effects were more pronounced at 200 kHz compared to a 50 kHz TTFields. Similar reductions in Ca activity were observed in patient-derived tumoroids. In brain tumor organoids, TTFields significantly reduced tumor cell proliferation and infiltration.
Our comprehensive study provides new insights into the multiple effects of Inovitro-modeled TTFields on glioma progression, morphology and network dynamics in vitro. Future in vivo studies to verify our in vitro findings may provide the basis for a deeper understanding and optimization of TTFields as a therapeutic modality in the treatment of GB.
本研究调查肿瘤治疗电场（TTFields）对胶质母细胞瘤恶性肿瘤关键驱动因素——肿瘤微管（TM）形成——以及对肿瘤细胞网络功能和整体完整性的生物学效应。
使用原发性胶质母细胞瘤细胞（GBC）培养物（S24、BG5或T269）的二维单培养GB细胞网络模型（2DTM），我们评估了TTFields对肿瘤网络的细胞密度、互连性和结构完整性的影响。我们还分析了钙（Ca）瞬态动力学和网络形态，在患者来源的肿瘤类器官和脑肿瘤类器官中验证了研究结果。
在2DTM分析中，TTFields使细胞密度降低了85 - 88%，并破坏了网络互连性，特别是在具有多个TM的细胞中。在5 - 6%的处理细胞中出现了“弯曲TM”表型，在对照中很少见。Ca瞬态受到显著损害，S24中全局Ca活性降低了51 - 83%，活跃和周期性细胞减少了50%以上，细胞间协同活性降低了52%，在BG5 GBCs中几乎完全丧失。与50kHz的TTFields相比，在200kHz时这些效应更明显。在患者来源的肿瘤类器官中也观察到了类似的Ca活性降低。在脑肿瘤类器官中，TTFields显著降低了肿瘤细胞增殖和浸润。
我们的综合研究为体外模拟的TTFields对胶质瘤进展、形态和网络动力学的多种影响提供了新的见解。未来的体内研究以验证我们的体外研究结果，可能为更深入理解和优化TTFields作为治疗GB的一种治疗方式提供基础。
