肿瘤治疗电场在肿瘤治疗中的应用和机制研究进展

Research progress in the application and mechanism of tumor treating fields in cancer treatment

[背景]肿瘤治疗领域缺乏高效、安全的非侵入式治疗方法.近年来,肿瘤治疗电场(tumor treating fields,TTFields)作为一种新兴的非侵入性物理治疗技术,通过释放中频、低强度的交变电场有效抑制肿瘤生长,引发的副作用较小.[进展]目前TTFields已被广泛应用于各类肿瘤治疗的临床研究中,包括脑胶质瘤、间皮质瘤、非小细胞肺癌、胰腺癌、卵巢癌、肝癌及胃癌等.TTFields通过向生物分子施加生物物理力,扰乱肿瘤细胞的生物学功能从而抑制其生长,但具体分子机制尚不明确.为研究TTFields在肿瘤治疗中的分子机制,研究人员通过设计和搭建不同电极和交变电场发生平台,在体外研究TTFields对肿瘤细胞的作用机制.研究发现TTFields干扰细胞分裂、DNA修复、自噬、细胞迁移和细胞膜通透性等生物学过程,也影响血脑屏障、血管生成和肿瘤免疫等肿瘤微环境.[展望]本文回顾了近年来TTFields在肿瘤治疗中的应用、用于体外研究的电极设计和电场发生平台,及其潜在的抗肿瘤机制.然而,TTFields抑制肿瘤生长的分子机制仍需深入研究,评估其对能够自我更新的非肿瘤细胞和终端分化细胞的影响,以减少可能的副作用.这些研究将有助于提升TTFields的治疗潜力,为更多恶性肿瘤的治疗开辟新的可能性.

[Background]Cells possess intrinsic electrical properties,and endogenous direct-current electric fields(DC-EFs)play crucial roles in various biological processes,such as embryogenesis and tissue regeneration.Various biological behaviors,including proliferation,adhesion,differentiation,polarity,and migration,are influenced by environmental alternating electric fields(AEFs).Direct low-frequency AEFs(<1 kHz)affect the polarization of cell membranes and induce excitatory or inhibitory effects on electrically excitable tissues.High-frequency AEFs(MHz range)do not induce membrane polarization but instead cause rapid oscillation of polar molecules,leading to tissue heating.Intermediate-frequency AEFs have been employed in various daily life applications,such as wireless power transfer(WPT),high-frequency induction(HFI)welding in industries,and medical therapies like cancer treatment.Notably,intermediate-frequency(100300 kHz)AEFs with low intensity(13 V/cm)have been found to specifically impair the growth of cancer cells.These electric fields,also known as tumor treating fields(TTFields),are delivered by transducer arrays placed on the skin close to the tumor and act regionally and noninvasively to inhibit tumor growth.TTFields have demonstrated effectiveness in inhibiting tumor growth while posing a lower risk of severe adverse effects(SAEs).[Progress]TTFields are currently being widely applied in the treatment of various cancer types,including glioblastoma(GBM),meningioma,non-small cell lung cancer(NSCLC),pancreatic cancer,ovarian cancer,liver cancer,and gastric cancer.These TTFields have demonstrated the ability to sensitize cancer cells to chemotherapy,targeted therapy,and radiotherapy.Combining TTFields with other treatment modalities has demonstrated potential benefits.Despite promising reports on the therapeutic potential of TTFields for cancer treatment,the precise underlying mechanisms are not yet fully understood.It is hypothesized that TTFields may inhibit tumor cell growth by disrupting the biological functions of cancer cells through the application of biophysical forces on various biological molecules.Under the influence of TTFields,charged particles oscillate according to the direction of the electric field,while dipolar particles align their polarity and migrate toward areas of higher field intensity,a phenomenon known as dielectrophoresis.This TTFields-induced dynamic rearrangement of highly polar macromolecules and organelles within cells is thought to contribute to the anti-cancer effects of TTFields.To explore the mechanisms of TTFields-dependent anti-tumor effects,researchers have designed and developed diverse types of electrodes and platforms to generate TTFields,including insulated wire electrodes,cell culture microfluidic devices embedded with stimulating electrodes,electrically insulated ceramic electrodes,Ag/AgCl electrodes,electrically isolated copper foils,and ultrasound-powered tumor treating devices(UP-TTD).These platforms can be used in cell culture models and animal models,facilitating the study of the effects of TTFields on tumor cell growth in vitro.By employing these various platforms,TTFields treatment has been shown to interfere with various biological processes,such as cell division,DNA repair,autophagy,cell migration,and cell membrane permeability.Additionally,TTFields have been found to impact the tumor microenvironment,affecting parameters like the blood-brain barrier,angiogenesis,and anti-tumor immune responses.However,the functional relationships between these biological processes in response to TTFields,as well as the underlying molecular mechanisms,require further investigation.[Perspective]This article provides an overview of recent advancements in TTFields applications in cancer treatment,including key electrode designs and platforms for generating TTFields in vitro.It explores the potential mechanisms underlying TTFields anti-tumor effects.While the anti-tumor properties of TTFields have been extensively studied,it is also crucial to consider their impact on healthy,non-cancerous cells.In brain cancer therapy,neurons,microglia,astrocytes,and oligodendrocytes within the tumor microenvironment are exposed to TTFields,necessitating further investigation into their responses to these fields.Moreover,future studies should evaluate the combination of TTFields with complementary approaches,such as traditional Chinese medicine,to explore potential additive or synergistic effects.By providing a comprehensive review of current progress and future directions in TTFields-based cancer therapy,this article aims to assist researchers and clinicians in developing more precise and effective AEF-based treatments for cancer.