Medical gas plasma augments bladder cancer cell toxicity in preclinical models and patient-derived tumor tissues,Journal of Advanced Research

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Medical gas plasma augments bladder cancer cell toxicity in preclinical models and patient-derived tumor tissues
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2022-08-03 , DOI: 10.1016/j.jare.2022.07.012
Nadine Gelbrich ₁ , Lea Miebach ₂ , Julia Berner ₃ , Eric Freund ₂ , Fariba Saadati ₄ , Anke Schmidt ₅ , Matthias Stope ₆ , Uwe Zimmermann ₇ , Martin Burchardt ₇ , Sander Bekeschus ₅

Affiliation

Clinic and Policlinic for Urology, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany; ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany.
ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany; Clinic and Policlinic for General, Visceral, Thoracic, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany.
ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany; Clinic and Policlinic for Oral, Maxillofacial, and Plastic Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany.
ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany; Clinic and Policlinic of Dermatology and Venerology, Rostock University Medical Center, Stempelstr. 13, 18057 Rostock, Germany.
ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany.
Department of Gynecology and Gynecological Oncology, University Hospital Bonn, 53127 Bonn, Germany.
Clinic and Policlinic for Urology, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany.

Introduction

Medical gas plasma therapy has been successfully applied to several types of cancer in preclinical models. First palliative tumor patients suffering from advanced head and neck cancer benefited from this novel therapeutic modality. The gas plasma-induced biological effects of reactive oxygen and nitrogen species (ROS/RNS) generated in the plasma gas phase result in oxidation-induced lethal damage to tumor cells.

Objectives

This study aimed to verify these anti-tumor effects of gas plasma exposure on urinary bladder cancer.

Methods

2D cell culture models, 3D tumor spheroids, 3D vascularized tumors grown on the chicken chorion-allantois-membrane (CAM) in ovo, and patient-derived primary cancer tissue gas plasma-treated ex vivo were used.

Results

Gas plasma treatment led to oxidation, growth retardation, motility inhibition, and cell death in 2D and 3D tumor models. A marked decline in tumor growth was also observed in the tumors grown in ovo. In addition, results of gas plasma treatment on primary urothelial carcinoma tissues ex vivo highlighted the selective tumor-toxic effects as non-malignant tissue exposed to gas plasma was less affected. Whole-transcriptome gene expression analysis revealed downregulation of tumor-promoting fibroblast growth factor receptor 3 (FGFR3) accompanied by upregulation of apoptosis-inducing factor 2 (AIFm2), which plays a central role in caspase-independent cell death signaling.

Conclusion

Gas plasma treatment induced cytotoxicity in patient-derived cancer tissue and slowed tumor growth in an organoid model of urinary bladder carcinoma, along with less severe effects in non-malignant tissues. Studies on the potential clinical benefits of this local and safe ROS therapy are awaited.

中文翻译：

医用气体等离子体增强临床前模型和患者来源的肿瘤组织中的膀胱癌细胞毒性

介绍

医用气体等离子疗法已在临床前模型中成功应用于多种类型的癌症。首批患有晚期头颈癌的姑息性肿瘤患者受益于这种新型治疗方式。在等离子体气相中产生的活性氧和氮物质 (ROS/RNS) 的气体等离子体诱导生物效应导致氧化诱导的对肿瘤细胞的致死损伤。

目标

本研究旨在验证气体等离子体暴露对膀胱癌的抗肿瘤作用。

方法

使用2D 细胞培养模型、3D 肿瘤球体、在卵内鸡绒毛膜尿囊膜 (CAM) 上生长的 3D 血管化肿瘤，以及离体患者来源的原发性癌组织气体等离子处理。

结果

气体等离子体处理导致 2D 和 3D 肿瘤模型中的氧化、生长迟缓、运动抑制和细胞死亡。在卵内生长的肿瘤中也观察到肿瘤生长显着下降。此外，离体原发性尿路上皮癌组织的气体等离子体处理结果突出了选择性肿瘤毒性作用，因为暴露于气体等离子体的非恶性组织受到的影响较小。全转录组基因表达分析显示，肿瘤促进成纤维细胞生长因子受体 3 (FGFR3) 的下调伴随着凋亡诱导因子 2 (AIFm2) 的上调，AIFm2 在半胱天冬酶非依赖性细胞死亡信号传导中起着核心作用。