A bioelectric model of carcinogenesis, including propagation of cell membrane depolarization and reversal therapies

Abstract

As the main theory of carcinogenesis, the Somatic Mutation Theory, increasingly presents difficulties to explain some experimental observations, different theories are being proposed. A major alternative approach is the Tissue Organization Field Theory, which explains cancer origin as a tissue regulation disease instead of having a mainly cellular origin. This work fits in the latter hypothesis, proposing the bioelectric field, in particular the cell membrane polarization state, and ionic exchange through ion channels and gap junctions, as an important mechanism of cell communication and tissue organization and regulation. Taking into account recent experimental results and proposed bioelectric models, a computational model of cancer initiation was developed, including the propagation of a cell depolarization wave in the tissue under consideration. Cell depolarization leads to a change in its state, with the activation and deactivation of several regulation pathways, increasing cell proliferation and motility, changing its epigenetic state to a more stem cell-like behavior without the requirement of genomic mutation. The intercellular communication via gap junctions leads, in certain circumstances, to a bioelectric state propagation to neighbor cells, in a chain-like reaction, till an electric discontinuity is reached. However, this is a reversible process, and it was shown experimentally that, by implementing a therapy targeted on cell ion exchange channels, it is possible to reverse the state and repolarize cells. This mechanism can be an important alternative way in cancer prevention, diagnosis and therapy, and new experiments are proposed to test the presented hypothesis.

Genetically-encoded BRET probes shed light on ligand bias–induced variable ion selectivity in TRPV1 and P2X5/7

“…Nonetheless, since excitable cell depolarization during spontaneous spiking will induce a K + -driving force, biased-enhanced K + permeability should reduce cellular input resistance and create a shunt that may powerfully hinder spontaneous spiking or bursting. Also, given the role that TRPV1 may play in the regulation of cancerous and healthy cell proliferation ( 50 – 52 ), and knowing that membrane depolarization is a prerequisite for cell division and proliferation ( 53 ), biased cationic selectivity in TRP ion channels may therefore occur in TRPV1 depending on the cell proliferation state. Finally, it is well known that hyperthermia occurs in a variety of mammalian organisms, including human, mouse, and rat, following systemic administration of many of the TRPV1 antagonists, including BCTC and AMG517.…”

A computational model of organism development and carcinogenesis resulting from cells’ bioelectric properties and communication

“…The expansion and stability of a generic two-dimensional tissue, a single layer of cells, was implemented in a computational model, a cellular automaton, to describe the dynamics and organization of a hypothetical organism. The cells’ bioelectric properties and state are responsible for coordination of development and homeostasis, and they follow approximately the model developed by Cervera et al, described in detail in 56 – 58 , and adapted and used in a previous work 59 . Cells can exchange ions with the extracellular medium by collective depolarization and polarization ion channels, and the intercellular communication is described by a universal gap junction.…”

Bioelectric Dysregulation in Cancer Initiation, Promotion, and Progression

“…Recently, Carvalho developed a computational model of cancer initiation, including the propagation of a cell depolarization wave in the tissue under consideration ( 106 ). This model looks at an electrically connected single layer tissue in two and three dimensions and simulates ion exchange between cells as well as between cells and the extracellular environment.…”