Emerging cancer therapies: targeting physiological networks and cellular bioelectrical differences with non-thermal systemic electromagnetic fields in the human body – a comprehensive review

" Recent publications have emphasized physiological networks and the pivotal role of cellular bioelectrical properties in driving cell proliferation, and cell synchronization with implications for cancer therapy. Innovative treatments based on non-thermal radiofrequency electromagnetic fields (EMF) have been developed, exploiting the unique electrical nature of all cells, particularly cancer cells, that exhibit autonomous oscillations distinct from healthy counterparts." {Credits 1}

" This review illustrates the potential of targeting cellular dynamics using EMF as an emerging cancer treatment by exploring various aspects of EMF. We will begin by discussing how EMF, generated by biological processes, influence systemic network organization in the human body. We will provide examples of biological interactions and regulatory mechanisms modulated by EMF. Next, we explore the physical aspects of EMF within biological systems, covering topics such as signal propagation, interference in dynamic systems, and the electrophysiology associated with EMF. Additionally, we introduce several applications, such as pulsed or alternating electric, magnetic, and electromagnetic fields currently used in Medicine with a focus on locoregional targets, in contrast to EMF that provide a novel systemic oncology therapeutics. Finally, we discuss the direct effects of EMF at tissue, cellular and subcellular structures, presenting a comprehensive body of evidence from clinical and translational research. We end this review introducing EMF generator medical devices currently in clinical development, offering a future direction view for this promising novel field of oncology therapeutics." {Credits 1}

" Considering that neural oscillations involve very low energy (synaptic interactions), interaction strength of coupled oscillators would be mainly determined by spatial proximity and site of stimulation. However, microscopic oscillations result in the generation of field superpositions on a mesoscopic scale that also superpose with all the other produced oscillators and become detectable at the macroscopic scale. For this reason, we hypothesize that the frequency of oscillation (fundamental frequencies) is the fundamental component for understanding the patterns of synchronization, resonance, and chaos." {Credits 1}

" In the central nervous system, for instance, a stratified hierarchy of endogenous EMF permeates the entirety of human physiology, extending from the cerebral cortex through deep brain structures and into an extensive extracerebral network distributed throughout the body. This organization of EMF is postulated to orchestrate and modulate neural activities in peripheral neural assemblies and other tissues, including those in the stomach and heart, synchronizing them with the cerebral rhythmic patterns." {Credits 1}

" The interaction (e.g., coupling) of the different sources of endogenous EMF is represented by a complex system characterized as non-linear, non-homogenous, anisotropic, non-stationary, and far-from-thermodynamic equilibrium (Hales, 2014). The totality of the generated EMF permeates the tissue, including all intracellular and extracellular spaces. As a result, in a living organism under normal physiological conditions, those fields exist as a seamless unity regardless of their sources. In the case of pathologies, this highly dynamically ordered state of biological matter may undergo a breakdown of global synchronization. This is a very important paradigm of our network approach." {Credits 1}

" Bioelectromagnetic fields or endogenous EMF are involved in the synchronization of regulatory processes by sending clear “signals” arising from specific coherent atomic/molecular/cell/tissue/organ-level sources (Hales, 2014). This synchronized steady state is known as the “electromagnetic homeostasis” (De Ninno and Pregnolato, 2017). This concept has been accepted by a number of researchers, however, the understanding of the complexity of those physiological network relations expressing non-linear behaviors and their topology is still a challenge (Bartsch et al., 2015; Uthamacumaran, 2021; Sun et al., 2022; Scholkmann, 2015; Limansky et al., 2014). One example of network physiology regulation on different time scales is the cross-frequency coupling of the brain (Canolty and Knight, 2010)." {Credits 1}

" Ionic currents flow into and out of a neuron, causing changes in the extracellular space (ECS) potential that can then influence the excitability of other nearby neurons close by. This type of signaling is known as ephaptic signaling, now considered relevant for neuronal synchronization (Han et al., 2018). Moreover, the ECS gap occupies approximately one-fifth of the brain’s volume, structured in a web filled with interstitial fluid. The ECS can be viewed as a container of ions used for electrical activity (Hrabetova et al., 2018). ECS occupies a narrow space in the synapse and produces EMF (Hales, 2014). The intracellular space (ICS) and ECS are separated by a lipid bilayer membrane that possesses specific dielectric properties (material that is a poor conductor of electricity), dependent on its biochemical composition and EMF frequency (Dilger et al., 1979). Again, coherence is the fundamental element for the dynamic formation and interaction of EMF. The ion motion between those spaces through channels that are synchronized in position, direction and time produce synchronized currents. The resultant EMF are also coherent, and they influence the nearby space interacting with all other dipole moments (measure of the separation of positive and negative electrical charges within a system) and moving electric charges. … Under specific conditions, a polarization effect occurring in the regional ECS/ICS can lead to the generation of field superpositions on a mesoscopic scale. These EMF also superpose with all the other produced fields and become detectable at the macroscopic scale (e.g., organ level) (Hales, 2014)." {Credits 1}

" Electromagnetic waves travel in the direction perpendicular to the plane in which the electric field E and magnetic field B vectors oscillate over time. Electromagnetic wave propagation follows Maxwell’s equations and has a velocity equal to the speed of light in vacuum (Robert, 2022). The oscillating electric fields (EF) “accelerate” charged particles in alternating directions. The magnetic fields “align” magnetic moment possessing molecules (magnetic dipoles or spins) like a compass needle that aligns with the Earth’s magnetic fields. Magnetic fields also cause moving charges to rotate in so-called cyclotron orbits in the plane perpendicular to the magnetic field direction." {Credits 1}

" Amplitude modulation (AM) is essential as a primary method for EMF signal transmission. AM is carrying signals by changing the shape of the envelope for carrier frequency waves (Tuszynski and Costa, 2022). Importantly, AM signals may produce oscillatory perturbations that interact with biological rhythms at very low and even extremely low frequencies (Lewczuk et al., 2014). These interactions become more noticeable (e.g., recordable) when the target tissue emits rhythmic electrical signals from cells that naturally pulse at similar rates as the oscillations found in AM signals, which range from 1 to 100 Hz (Tuszynski and Costa, 2022; Bertagna et al., 2021; Sawicki and Schöll, 2024)." {Credits 1}

" It is understandable that normal and cancer cells would respond differently to the same EMF exposure since they are characterized by vastly different dielectric constants, electric conductivities and transmembrane potential gradients. The interaction between EMF and cellular bioelectrical systems is embedded within the body’s systemic framework (Freddolino and Tavazoie, 2012)." {Credits 1}

" Oscillatory patterns are synchronized across cellular populations in response to diverse biochemical and metabolic activities which provide functional advantages over static signaling inputs. Thus, essential molecules present in biological tissue such as ions, water molecules, proteins, nucleic acids, and lipids, possess either a net electrical charge or a dipole moment, often in periodic motion, hence can be affected by EMF (Fenwick, Esteban-Martín, and Salvatella, 2011)." {Credits 1}

" EMF induced synchronization is easier to demonstrate studying action potentials in excitable cells rather than in non-excitable cells. However, EMF induced synchronization of gene expression and metabolic pathways – though more challenging – can be also demonstrated in non-excitable cells (Del Olmo et al., 2023; Friesen, Baracos, and Tuszynski, 2015; Piszczek et al., 2022; Moraveji et al., 2016; Mousavi Maleki et al., 2022; Phillips, 1993; Zimmerman et al., 2012)." {Credits 1}

" Cancer cell behavior has been proposed to present damped EMF activities (Pokorný et al., 2020). Cancer often leads to the system expending more energy than it can replenish, resulting in a gradual reduction in oscillation amplitude and an increase in entropy (quantifies the degree of disorder or randomness in a system). Characteristic bioelectric behavior is one of the new accepted hallmarks of cancer and it is crucial for understanding how electrical signals and charges contribute to the onset, growth, and progression of cancer, and the emerging significance of bioelectricity in cancer proliferation and metastasis (Moreddu, 2024; Schwartz, Supuran, and Alfarouk, 2017; Hanahan and Weinberg, 2011). Cancer cells exhibit autonomous oscillations, deviating from normal rhythms observed in processes like glycolysis (a phenomenon known as the Warburg Effect whereby a shift occurs from the predominantly oxidative phosphorylation mode of energy production toward glycolysis) (Vander Heiden, Cantley, and Thompson, 2009; Rietman et al., 2013; Sawicki et al., 2022). This indicates a distinct signaling system in cancer cells compared to healthy ones. Furthermore, cancer can be conceptualized as exhibiting parasitic energy consumption, that leads to a dampening effect on the cellular electromagnetic field." {Credits 1}

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{Credits 1} 🎪 Costa FP, Wiedenmann B, Schöll E and Tuszynski J (2024) Emerging cancer therapies: targeting physiological networks and cellular bioelectrical differences with non-thermal systemic electromagnetic fields in the human body – a comprehensive review. Front. Netw. Physiol. 4:1483401. doi: 10.3389/fnetp.2024.1483401. © 2024 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 License.