Endogenous Voltage Potentials and the Microenvironment: Bioelectric Signals that Reveal, Induce and Normalize Cancer

Abstract

Cancer may be a disease of geometry: a misregulation of the field of information that orchestrates individual cells’ activities towards normal anatomy. Recent work identified molecular mechanisms underlying a novel system of developmental control: bioelectric gradients. Endogenous spatio-temporal differences in resting potential of non-neural cells provide instructive cues for cell regulation and complex patterning during embryogenesis and regeneration. It is now appreciated that these cues are an important layer of the dysregulation of cell: cell interactions that leads to cancer. Abnormal depolarization of resting potential (Vmem) is a convenient marker for neoplasia and activates a metastatic phenotype in genetically-normal cells in vivo. Moreover, oncogene expression depolarizes cells that form tumor-like structures, but is unable to form tumors if this depolarization is artificially prevented by misexpression of hyperpolarizing ion channels. Vmem triggers metastatic behaviors at considerable distance, mediated by transcriptional and epigenetic effects of electrically-modulated flows of serotonin and butyrate. While in vivo data on voltages in carcinogenesis comes mainly from the amphibian model, unbiased genetic screens and network profiling in rodents and human tissues reveal several ion channel proteins as bona fide oncogene and promising targets for cancer drug development. However, we propose that a focus on specific channel genes is just the tip of the iceberg. Bioelectric state is determined by post-translational gating of ion channels, not only from genetically-specified complements of ion translocators. A better model is a statistical dynamics view of spatial Vmem gradients. Cancer may not originate at the single cell level, since gap junctional coupling results in multi-cellular physiological networks with multiple stable attractors in bioelectrical state space. New medical applications await a detailed understanding of the mechanisms by which organ target morphology stored in real-time patterns of ion flows is perceived or mis-perceived by cells. Mastery of somatic voltage gradients will lead to cancer normalization or rebooting strategies, such as those that occur in regenerating and embryonic organs, resulting in transformative advances in basic biology and oncology.

Genome‐wide analysis reveals conserved transcriptional responses downstream of resting potential change in Xenopus embryos, axolotl regeneration, and human mesenchymal cell differentiation

“…; Zuberi et al. ; Chernet & Levin ; Yang & Brackenbury ). One important aspect of endogenous bioelectricity is resting potential or V mem (Levin ).…”

SMT and TOFT: Why and How They are Opposite and Incompatible Paradigms

“…Moreover, a study concluded that depolarization of a glycine receptorexpressing channel in Xenopus Laevis neural crest may induce a full metastatic melanoma without any involvement of a mutation, carcinogen, or DNA damage (Blackiston et al 2011). Deregulation of the bioelectric environment may rewire protein interaction networks (Taylor et al 2009), and comprehensive reviews of the role of bioelectric processes in cancer, highlighting how bioelectric activity is a constitutive partner of the morphogenetic field involved during cancer transformation, have also been published (Chernet and Levin 2013).…”

Energy transduction and signal averaging of fluctuating electric fields by a single protein ion channel

“…Ion channel selectivity and electric field-sensing are crucial to bioelectrical activity. [18][19][20] The bioelectrical characteristics of commercially available protein ion channels and toxin poreformers can be used in bio-electronic interfaces and ionic a Dept. [18][19][20] The bioelectrical characteristics of commercially available protein ion channels and toxin poreformers can be used in bio-electronic interfaces and ionic a Dept.…”