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

" 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." {Credits 1}

" The current standard theory to explain tumorigenesis is the Somatic Mutation Theory (SMT) [1,2], which proposes that the origin of cancer can be interpreted by an accumulation of genetic mutations, in particular on tumor suppressor genes and oncogenes, that are passed to their cell descendants. Tumor development is then a multistep process, where successive mutations produce advantageous biological capabilities [3]. This is the widely accepted theory of cancer initiation and it can explain many cancer features, from hereditary cancers to the late onset on life of most of them, and the success of some therapies targeting mutant genes [1]. However, there are many experimental results that contradict SMT, in particular the existence of non-genotoxic carcinogens, like chloroform and p-dichlorobenzene [4], inducing cancer without DNA alterations, and no mutations are detected in some tumors [5]. Also, changes in the DNA methylation pattern, not in its sequence (only the rate of proteins production, not their composition), are found in some cancerous lesions [1], and it is possible to induce carcinogenesis without mutagenesis by the introduction of foreign materials into body tissues [6]." {Credits 1}

" The bioelectrical communication is then a mechanism for tissue cells homeostasis but also, in case of a major perturbation, a process driving a global cells’ state change. This phenomena is also present during organism development, where spatial and temporal variations in the distribution of membrane electrical potentials are responsible for patterns’ formation, and are involved in such fundamental processes as eye formation, limb regeneration or anatomical axes definition [35]. But a stress (carcinogenic) event can overwhelm tissue control feedback systems and cells have their epigenetic program modified, due to the strong bioelectric coupling with neighbor cells via gap junctions and, eventually, also by intercellular electric fields." {Credits 1}

{Credits 1} 🎪 Carvalho, J. A bioelectric model of carcinogenesis, including propagation of cell membrane depolarization and reversal therapies. Sci Rep 11, 13607 (2021). This is an open access article distributed under the Creative Commons Attribution International License.