Bioelectric Dysregulation in Cancer Initiation, Promotion, and Progression

Bioactuators are a class of devices that can be used to modify cell behavior by delivering directly biophysical signals such as electrophoretic delivery of ions and small molecules targeting specific cell locations (14). Additionally, a variety of nanomaterials have been developed for reading and writing bioelectric cues in tissue. These include biocompatible piezoelectric materials and nanoparticles that alter the resting potential of cells by contact, without the use of transgenes (170–173). Warren and Payne determined that nanoparticles with amine-modified surfaces induced significant depolarization in both, Chinese Hamster Ovary (CHO) cells and HeLa cells (173). Conductive polymers are another class of materials that can stimulate cells or tissue cultured upon them (174–176) by applying an electrical signal. Conductive polymers used in tissue engineering include conductive nanofibers, conductive hydrogels, conductive composite films, and conductive composite scaffolds fabricated using methods such as electrospinning, coating, or deposition by in situ polymerization (177). For instance, Jayaram et al. used PEDOT : PSS conducting polymer microwires to depolarize cells and achieve a more positive membrane potential in E. coli cells (170). Thourson and Payne also demonstrated the use of PEDOT : PSS microwires to control action potentials of cardiomyocytes (178). Conductive polymer microwires thus provide a minimally invasive platform to control electrical properties of cells with high spatial precision. Detailed reviews on conductive polymers have been previously published (177, 179).

As mentioned previously, treatment with ivermectin is another way to control the transmembrane potential of a select group of cells by manipulating of endogenous chloride channels ( Figure 4A ). Ivermectin targets GlyR-expressing cells and hence opens their chloride channels. Chloride ions can then be made to enter or exit the GlyR-expressing cells by manipulating the external chloride levels, thus controlling their transmembrane potential (7). For instance, a low level of chloride in the external medium would cause chloride ions to exit the cell and into the medium, hence depolarizing the cell. Lobikin et al. employed this method in frog models to regulate the membrane potential of a specific group of cells expressing GlyCl channels to desired levels and study the consequences on metastasis and tumorigenesis in vivo.

Another potential way to manipulate the bioelectric properties of cells is by controlling the mechanosensitive Ca2+-permeable Piezo channels which have emerged as major transducers of mechanical stress into Ca2+ dependent signals. These mechanosensitive Piezo channels expressed on the plasma membrane are gated by various mechanical stimuli such as stiffness, compression, tension forces, and shear stress. Channel activation then allows a Ca2+ influx into the cytoplasm which then mediates the cell polarity ( Figure 4B ). Piezo1 may also be pharmacologically activated by agonists such as Jedi1, Jedi2 and Yoda1 or inhibited by channel pore blockers, competitive antagonists, and peptides such as Ruthenium Red, GsMTx-4, Dooku1 and Aß peptides which distort the membrane mechanical properties (87). Han et al. demonstrated that activation of Piezo1 via mechanical stimuli in 1 μm using a heat-polished glass probe controlled by a piezo electric device or via agonist Yoda1 mediated Ca2+ influx in pancreatic cancer cells, resulting into a more depolarized state (88).

Extracellular vesicles (EVs) facilitate inter-cellular communication via delivery of proteins and nucleic acids, including microRNA (miRNA) and mRNA (180). EVs-mediated communication is vital during the establishment of planar cell polarity and the developmental patterning of tissues (181). EVs are particularly enriched in the tumor microenvironment (182, 183) and as mentioned in the previous sections of this paper, they play a special role in cancer development and progression. In a recent study, Fukuta et al. demonstrated that external stimuli such as low levels of electric field treatment that activate intracellular signaling would likely increase exosome secretion from the cells. It was seen that an electric field of 0.34 mA/cm2 increases the secretion of these EVs from cultured cells of murine melanoma B16F1 and murine fibroblast 3T3 Swiss Albino without compromising their quality (180). These results together indicate that the bioelectric dysregulation or depolarization of cells that occurs during cancer may be responsible for the upregulation of EVs in the cancer tumor microenvironment. At the same time, the increase in production of EVs plays a role in disrupting the bioelectric homeostasis, forming a feedback loop. The change in cell state and EV production along with the interdependence of the two are major mechanisms responsible for the bioelectric dysregulation of cancer.

Bioelectric signaling is a growing field of study that takes us a step closer to understanding cancer as a disease, all the way from initiation to metastasis. A lot is known about cancer and its biology as per the somatic mutation theory. On the other hand, the role of electric fields in cancer processes, while strongly established over the last few decades, needs further investigation. Understanding the bioelectric mechanisms underlying cancer is especially important since it will allow us to develop new biomedical and bioengineering tools and techniques as per the tissue organization field theory. These new engineering tools, along with the existing biological knowledge will enhance our understanding of cancer and enable the development of novel treatments for patients.

Another exciting area of study is the interplay between the bioelectric dysregulation and enhancement of extracellular vesicles (EVs) within the context of the cancer microenvironment. It has been well established that EVs play a significant role in facilitating the signaling pathways involved in all processes of carcinogenesis. This paper provides a detailed review of the current knowledge about bioelectric dysregulation that underlies different processes of cancer. However, little is known about the interdependence of these two mechanisms. Furthermore, EVs, especially exosomes, have been proven to have a role in therapeutic strategies for cancer. Understanding this crosstalk will not only enhance our knowledge of cancer, but also help develop efficient exosome-based cancer immunotherapies and drug delivery vehicles.

MS wrote the main manuscript text and prepared all figures. LE gave suggestions and ideas on the literature search and manuscript writing. All authors contributed to the article and approved the submitted version.

This work has been funded by the National Science Foundation NSF CAREER ECCS (2046037).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Figures 1 and 4A were created with BioRender.com. Figure 2 was adapted from “Tumor Microenvironment 2”, by BioRender.com (2021). Figure 3 was adapted from “Overview of Metastatic Cascade”, by BioRender.com (2021). Figure 4 B was adapted from “PIEZO Channels: How Do They Allow Mechanosensation?”, by BioRender.com. (2021). Figures 2 , 3 , and 4B were retrieved from https://app.biorender.com/biorender-templates.

EV, extracellular vesicle; TME, tumor microenvironment; Vmem, membrane potential; EF, electric field; SMT, somatic mutation theory; TOFT, tissue organization field theory; HMEC, human mammary epithelial cell; MCF7, estrogen-receptor-positive breast cancer cell line; MDA-MB-231, estrogen-receptor-negative breast cancer cell line; ECM, extracellular matrix; EMT, epithelial mesenchymal transition; CAF, cancer associated fibroblast; GlyCl, glycine-gated chloride channel; VGCC, voltage gated calcium channel; VGSC, voltage gated sodium channel; EAG, ether-à-go-go K+ channel; TRP, transient receptor potential; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; Pl3K/Akt, phosphatidylinositol 3-kinase/protein kinase B; MEK, mitogen-activated ERK kinase; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; GBM, glioblastoma multiforme; GSK-3ß, glycogen synthase kinase-3 ß; ITLS, induced tumor like structure; MCF10A, normal breast epithelium cell line; CTC, circulating tumor cell; DTC, disseminated tumor cell; mRNA, messenger RNA; miRNA, micro RNA; B16F1, murine melanoma cell line; 3T3, murine fibroblast cell line; OECT, organic electrochemical transistor; CHO, Chinese hamster ovary; PEDOT : PSS, poly(3,4-ethylenedioxythiophene): polystyrene sulfonate.