Direct-current (DC) electric fields are present in all developing and regenerating animal tissues, yet their existence and potential impact on tissue repair and development are largely ignored. This is primarily due to ignorance of the phenomenon by most researchers, some technically poor early studies of the effects of applied fields on cells, and widespread misunderstanding of the fundamental concepts that underlie bioelectricity. This review aims to resolve these issues by describing: 1) the historical context of bioelectricity, 2) the fundamental principles of physics and physiology responsible for DC electric fields within cells and tissues, 3) the cellular mechanisms for the effects of small electric fields on cell behavior, and 4) the clinical potential for electric field treatment of damaged tissues such as epithelia and the nervous system.

/pdf/controlling-cell-behavior-electrically-current-views-and-4ac74x4sxy.pdf

Controlling Cell Behavior Electrically: Current Views and Future Potential

Despite its recognized value in detecting and characterizing breast disease, X-ray mammography has important limitations that motivate the quest for alternatives to augment the diagnostic tools that are currently available to the radiologist. The rationale for pursuing electromagnetic methods is strong given the data in the literature, which show that the electromagnetic properties of breast malignancy are significantly different than normal in the high megahertz to low gigahertz spectral range, microwave illumination can effectively penetrate the breast at these frequencies, and the breast is a small readily accessible tissue volume, making it an ideal site for deploying advanced near-field imaging concepts that exploit model-based image reconstruction methodology. In this paper a clinical prototype of a microwave imaging system, which actively illuminates the breast with a 16-element transceiving monopole antenna array in the 300-1000 MHz range, is reported. Microwave exams have been delivered to five women through a water-coupled interface to the pendant breast with the participant positioned prone on an examination table. This configuration has been found to be a practical, comfortable approach to microwave breast imaging. Sessions lasted 10-15 min per breast and included full tomographic data acquisition at seven different array heights beginning at the chest wall and moving anteriorly toward the nipple for seven different frequencies at each array position. This clinical experience appears to be the first report of active near-field microwave imaging of the breast and is certainly the first attempt to exploit model-based image reconstructions from in vivo breast data in order to convert the measured microwave signals into spatial maps of electrical permittivity and conductivity. While clearly preliminary, the results are encouraging and have supplied some interesting findings. Specifically, it appears that the average relative permittivity of the breast as a whole correlates with radiologic breast density categorization and may be considerably higher than previously published values, which have been based on ex vivo tissue specimens.

A clinical prototype for active microwave imaging of the breast

Purpose: Ion channel activity is involved in several basic cellular behaviors that are integral to metastasis (e.g., proliferation, motility, secretion, and invasion), although their contribution to cancer progression has largely been ignored. The purpose of this study was to investigate voltage-gated Na + channel (VGSC) expression and its possible role in human breast cancer. Experimental Design: Functional VGSC expression was investigated in human breast cancer cell lines by patch clamp recording. The contribution of VGSC activity to directional motility, endocytosis, and invasion was evaluated by in vitro assays. Subsequent identification of the VGSC α-subunit(s) expressed in vitro was achieved using reverse transcription-PCR, immunocytochemistry, and Western blot techniques and used to investigate VGSCα expression and its association with metastasis in vivo . Results: VGSC expression was significantly up-regulated in metastatic human breast cancer cells and tissues, and VGSC activity potentiated cellular directional motility, endocytosis, and invasion. Reverse transcription-PCR revealed that Na v 1.5, in its newly identified “neonatal” splice form, was specifically associated with strong metastatic potential in vitro and breast cancer progression in vivo . An antibody specific for this form confirmed up-regulation of neonatal Na v 1.5 protein in breast cancer cells and tissues. Furthermore, a strong correlation was found between neonatal Na v 1.5 expression and clinically assessed lymph node metastasis. Conclusions: Up-regulation of neonatal Na v 1.5 occurs as an integral part of the metastatic process in human breast cancer and could serve both as a novel marker of the metastatic phenotype and a therapeutic target.

https://clincancerres.aacrjournals.org/content/clincanres/11/15/5381.full.pdf

Voltage-Gated Sodium Channel Expression and Potentiation of Human Breast Cancer Metastasis

Controlling angiogenesis is crucial. Growth factors and cytokines are key regulators but a full understanding remains elusive. Endogenous electrical potential differences exist within and around the vasculature, both in relation to blood flow and in situations where active angiogenesis occurs, such as wound healing, development and tumor growth. Recent work shows that electrical stimulation induces significant angiogenesis in vivo, through enhanced vascular endothelial growth factor (VEGF) production by muscle cells. We report that applied electric fields (EFs) of small physiological magnitude directly stimulate VEGF production by endothelial cells in culture without the presence of any other cell type. EFs as low as 75-100 mV mm-1 (1.5-2.0 mV across an endothelial cell) directed the reorientation, elongation and migration of endothelial cells in culture. These pre-angiogenic responses required VEGF receptor activation and were mediated through PI3K-Akt and Rho-ROCK signaling pathways, resulting in reorganization of the actin cytoskeleton. This indicates that endogenous EFs might play a role in angiogenesis in vivo by stimulating the VEGF receptor signaling pathway, to induce key pre-angiogenic responses. In addition, it raises the feasibility of using applied EFs to initiate and guide angiogenesis through direct effects on endothelial cells.

/pdf/electrical-stimulation-directly-induces-pre-angiogenic-2gisgyk3gp.pdf

Electrical stimulation directly induces pre-angiogenic responses in vascular endothelial cells by signaling through VEGF receptors

Cells undergo a variety of physiological processes, including division, migration and differentiation, under the influence of endogenous electrical cues, which are generated physiologically and pathologically in the extracellular and sometimes intracellular spaces. These signals are transduced to regulate cell behaviours profoundly, both in vitro and in vivo. Bioelectricity influences cellular processes as fundamental as control of the cell cycle, cell proliferation, cancer-cell migration, electrical signalling in the adult brain, embryonic neuronal cell migration, axon outgrowth, spinal-cord repair, epithelial wound repair, tissue regeneration and establishment of left-right body asymmetry. In addition to direct effects on cells, electrical gradients interact with coexisting extracellular chemical gradients. Indeed, cells can integrate and respond to electrical and chemical cues in combination. This Commentary details how electrical signals control multiple cell behaviours and argues that study of the interplay between combined electrical and chemical gradients is underdeveloped yet necessary.

Electrical dimensions in cell science.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(97)10002-2.pdf

Electropotential measurements as a new diagnostic modality for breast cancer

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Electropotential measurements as a new diagnostic modality for breast cancer