Research progress in the application and mechanism of tumor treating fields in cancer treatment
[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(100-300 kHz)AEFs with low intensity(1-3 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.
intermediate frequency alternating electric fieldtumor treating fieldtumor treatment methodelectrodes designcombination therapy
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