{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T19:01:42Z","timestamp":1770490902345,"version":"3.49.0"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04564\/2020"],"award-info":[{"award-number":["UIDB\/04564\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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.<\/jats:p>","DOI":"10.1038\/s41598-021-92951-0","type":"journal-article","created":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T10:04:14Z","timestamp":1625047454000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A bioelectric model of carcinogenesis, including propagation of cell membrane depolarization and reversal therapies"],"prefix":"10.1038","volume":"11","author":[{"given":"Joao","family":"Carvalho","sequence":"first","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,6,30]]},"reference":[{"key":"92951_CR1","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1002\/bies.201100022","volume":"33","author":"DL Vaux","year":"2011","unstructured":"Vaux, D. L. In defense of the somatic mutation theory of cancer. BioEssays 33, 341\u2013343. https:\/\/doi.org\/10.1002\/bies.201100022 (2011).","journal-title":"BioEssays"},{"issue":"2","key":"92951_CR2","doi-asserted-by":"publisher","first-page":"dju405","DOI":"10.1093\/jnci\/dju405","volume":"107","author":"SG Baker","year":"2014","unstructured":"Baker, S. G. A cancer theory kerfuffle can lead to new lines of research. J. Natl. Cancer Inst. 107(2), dju405. https:\/\/doi.org\/10.1093\/jnci\/dju405 (2014).","journal-title":"J. Natl. Cancer Inst."},{"key":"92951_CR3","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","volume":"144","author":"D Hanahan","year":"2011","unstructured":"Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: The next generation. Cell 144, 646\u2013674. https:\/\/doi.org\/10.1016\/j.cell.2011.02.013 (2011).","journal-title":"Cell"},{"issue":"3","key":"92951_CR4","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/S0300-483X(02)00393-1","volume":"180","author":"A Mally","year":"2002","unstructured":"Mally, A. & Chipman J. K. Non-genotoxic carcinogens: early effects on gap junctions, cell proliferation and apoptosis in the rat.  Toxicology 180(3), 233\u2013248. https:\/\/doi.org\/10.1016\/S0300-483X(02)00393-1 (2002) .","journal-title":"Toxicology"},{"key":"92951_CR5","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1038\/nature13061","volume":"506","author":"R Versteeg","year":"2014","unstructured":"Versteeg, R. Tumours outside the mutation box. Nature 506, 438\u2013439. https:\/\/doi.org\/10.1038\/nature13061 (2014).","journal-title":"Nature"},{"issue":"3063","key":"92951_CR6","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1126\/science.118.3063.305","volume":"118","author":"BS Oppenheimer","year":"1953","unstructured":"Oppenheimer, B. S., Oppenheimer, E. T., Stout, A. P. & Danishefsky, I. Malignant tumors resulting from embedding plastics in rodents. Science 118(3063), 305\u20136. https:\/\/doi.org\/10.1126\/science.118.3063.305 (1953).","journal-title":"Science"},{"key":"92951_CR7","doi-asserted-by":"publisher","first-page":"136","DOI":"10.3389\/fncel.2020.00136","volume":"14","author":"VP Pai","year":"2020","unstructured":"Pai, V. P. et al. HCN2 channel-induced rescue of brain teratogenesis via local and long-range bioelectric repair. Front. Cell. Neurosci. 14, 136. https:\/\/doi.org\/10.3389\/fncel.2020.00136 (2020).","journal-title":"Front. Cell. Neurosci."},{"key":"92951_CR8","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.cell.2016.12.014","volume":"168","author":"J Humphries","year":"2017","unstructured":"Humphries, J. et al. Species-independent attraction to biofilms through electrical signaling. Cell 168, 200-209.e12. https:\/\/doi.org\/10.1016\/j.cell.2016.12.014 (2017).","journal-title":"Cell"},{"key":"92951_CR9","doi-asserted-by":"publisher","first-page":"e1004080","DOI":"10.1371\/journal.pgen.1004080","volume":"10","author":"S Perathoner","year":"2014","unstructured":"Perathoner, S. et al. Bioelectric signaling regulates size in zebrafish fins. PLoS Genet. 10, e1004080. https:\/\/doi.org\/10.1371\/journal.pgen.1004080 (2014).","journal-title":"PLoS Genet."},{"key":"92951_CR10","doi-asserted-by":"publisher","first-page":"e1309488","DOI":"10.1080\/19420889.2017.1309488","volume":"10","author":"E Pitcairn","year":"2017","unstructured":"Pitcairn, E. et al. Coordinating heart morphogenesis: a novel role for hyperpolarization-activated cyclic nucleotide-gated (HCN) channels during cardiogenesis in Xenopus laevis. Commun. Integr. Biol. 10, e1309488. https:\/\/doi.org\/10.1080\/19420889.2017.1309488 (2017).","journal-title":"Commun. Integr. Biol."},{"key":"92951_CR11","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.1242\/bio.025957","volume":"6","author":"VP Pai","year":"2017","unstructured":"Pai, V. P. et al. HCN4 ion channel function is required for early events that regulate anatomical left-right patterning in a nodal and lefty asymmetric gene expression-independent manner. Biol. Open 6, 1445\u20131457. https:\/\/doi.org\/10.1242\/bio.025957 (2017).","journal-title":"Biol. Open"},{"key":"92951_CR12","doi-asserted-by":"publisher","first-page":"043001","DOI":"10.1088\/2057-1739\/aa8548","volume":"3","author":"D Moore","year":"2017","unstructured":"Moore, D., Walker, S. I. & Levin, M. Cancer as a disorder of patterning information: Computational and biophysical perspectives on the cancer problem. Conv. Sci. Phys. Oncol. 3, 043001. https:\/\/doi.org\/10.1088\/2057-1739\/aa8548 (2017).","journal-title":"Conv. Sci. Phys. Oncol."},{"key":"92951_CR13","doi-asserted-by":"publisher","first-page":"519","DOI":"10.3389\/fphys.2014.00519","volume":"5","author":"BT Chernet","year":"2015","unstructured":"Chernet, B. T., Fields, C. & Levin, M. Long-range gap junctional signaling controls oncogene-mediated tumorigenesis in Xenopus laevis embryos. Front. Physiol. 5, 519. https:\/\/doi.org\/10.3389\/fphys.2014.00519 (2015).","journal-title":"Front. Physiol."},{"key":"92951_CR14","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1152\/physrev.00044.2016","volume":"98","author":"N Prevarskaya","year":"2018","unstructured":"Prevarskaya, N., Skryma, R. & Shuba, Y. Ion channels in cancer: Are cancer hallmarks oncochannelopathies?. Physiol. Rev. 98, 559\u2013621. https:\/\/doi.org\/10.1152\/physrev.00044.2016 (2018).","journal-title":"Physiol. Rev."},{"issue":"3","key":"92951_CR15","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/j.ccell.2017.02.005","volume":"31","author":"B Boilly","year":"2017","unstructured":"Boilly, B., Faulkner, S., Jobling, P. & Hondermarck, H. Nerve dependence: From regeneration to cancer. Cancer Cell 31(3), 342\u2013354. https:\/\/doi.org\/10.1016\/j.ccell.2017.02.005 (2017).","journal-title":"Cancer Cell"},{"issue":"12","key":"92951_CR16","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1016\/j.tins.2016.10.002","volume":"39","author":"JL Saloman","year":"2016","unstructured":"Saloman, J. L., Albers, K. M., Rhim, A. D. & Davis, B. M. Can stopping nerves, stop cancer? Trends Neurosci. 39(12), 880\u2013889. https:\/\/doi.org\/10.1016\/j.tins.2016.10.002 (2016).","journal-title":"Trends Neurosci."},{"key":"92951_CR17","doi-asserted-by":"publisher","first-page":"646","DOI":"10.3389\/fonc.2018.00646","volume":"8","author":"M Sinyuk","year":"2018","unstructured":"Sinyuk, M., Mulkearns-Hubert, E. E., Reizes, O. & Lathia, J. Cancer connectors: Connexins, gap junctions, and communication. Front. Oncol. 8, 646. https:\/\/doi.org\/10.3389\/fonc.2018.00646 (2018).","journal-title":"Front. Oncol."},{"key":"92951_CR18","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.3389\/fonc.2019.01209","volume":"9","author":"C Zhang","year":"2019","unstructured":"Zhang, C. et al. Prognostic and clinic pathological value of Cx43 expression in glioma: A meta-analysis. Front. Oncol. 9, 1209. https:\/\/doi.org\/10.3389\/fonc.2019.01209 (2019).","journal-title":"Front. Oncol."},{"key":"92951_CR19","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/s41567-019-0765-4","volume":"16","author":"HM McNamara","year":"2020","unstructured":"McNamara, H. M. et al. Bioelectrical domain walls in homogeneous tissues. Nat. Phys. 16, 357\u2013364. https:\/\/doi.org\/10.1038\/s41567-019-0765-4 (2020).","journal-title":"Nat. Phys."},{"issue":"3","key":"92951_CR20","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1002\/bies.201100136","volume":"34","author":"M Levin","year":"2012","unstructured":"Levin, M. Molecular bioelectricity in developmental biology: New tools and recent discoveries: control of cell behavior and pattern formation by transmembrane potential gradients. Bioessays 34(3), 205\u2013217. https:\/\/doi.org\/10.1002\/bies.201100136 (2012).","journal-title":"Bioessays"},{"key":"92951_CR21","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1146\/annurev-bioeng-071811-150114","volume":"14","author":"M Levin","year":"2012","unstructured":"Levin, M. & Stevenson, C. G. Regulation of cell behavior and tissue patterning by bioelectrical signals: Challenges and opportunities for biomedical engineering. Annu. Rev. Biomed. Eng. 14, 295\u2013323. https:\/\/doi.org\/10.1146\/annurev-bioeng-071811-150114 (2012).","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"92951_CR22","doi-asserted-by":"publisher","first-page":"185","DOI":"10.3389\/fphys.2013.00185","volume":"4","author":"M Yang","year":"2013","unstructured":"Yang, M. & Brackenbury, W. J. Membrane potential and cancer progression. Front. Physiol. 4, 185. https:\/\/doi.org\/10.3389\/fphys.2013.00185 (2013).","journal-title":"Front. Physiol."},{"key":"92951_CR23","doi-asserted-by":"publisher","first-page":"137-47","DOI":"10.1002\/jcp.21015","volume":"212","author":"H Lin","year":"2007","unstructured":"Lin, H. et al. Overexpression HERG K+ channel gene mediates cell-growth signals on activation of oncoproteins SP1 and NF-KB and inactivation of tumor suppressor Nkx3.1. J. Cell. Physiol. 212, 137\u201347. https:\/\/doi.org\/10.1002\/jcp.21015 (2007).","journal-title":"J. Cell. Physiol."},{"key":"92951_CR24","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.mrfmmm.2004.03.013","volume":"569","author":"RS Bindra","year":"2005","unstructured":"Bindra, R. S. & Glazer, P. M. Genetic instability and the tumor microenvironment: Towards the concept of microenvironment-induced mutagenesis. Mutat. Res. 569, 75\u201385. https:\/\/doi.org\/10.1016\/j.mrfmmm.2004.03.013 (2005).","journal-title":"Mutat. Res."},{"issue":"1","key":"92951_CR25","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s40487-017-0047-1","volume":"5","author":"A Adjiri","year":"2017","unstructured":"Adjiri, A. DNA mutations may not be the cause of cancer. Oncol. Ther. 5(1), 85\u2013101. https:\/\/doi.org\/10.1007\/s40487-017-0047-1 (2017).","journal-title":"Oncol. Ther."},{"issue":"2","key":"92951_CR26","doi-asserted-by":"publisher","first-page":"849","DOI":"10.3390\/cancers7020813","volume":"7","author":"VR Rao","year":"2015","unstructured":"Rao, V. R., Perez-Neut, M., Kaja, S. & Gentile, S. Voltage-gated ion channels in cancer cell proliferation. Cancers 7(2), 849\u2013875. https:\/\/doi.org\/10.3390\/cancers7020813 (2015).","journal-title":"Cancers"},{"issue":"11","key":"92951_CR27","doi-asserted-by":"publisher","first-page":"2364","DOI":"10.1002\/ijc.23125","volume":"121","author":"F Okada","year":"2007","unstructured":"Okada, F. Beyond foreign-body-induced carcinogenesis: Impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression. Int. J. Cancer 121(11), 2364\u201372. https:\/\/doi.org\/10.1002\/ijc.23125 (2007).","journal-title":"Int. J. Cancer"},{"issue":"10 Pt B","key":"92951_CR28","doi-asserted-by":"publisher","first-page":"2657-64","DOI":"10.1016\/j.bbamem.2014.11.004","volume":"1848","author":"SM Huber","year":"2015","unstructured":"Huber, S. M. et al. Role of ion channels in ionizing radiation-induced cell death. Biochim. Biophys. Acta 1848(10 Pt B), 2657\u201364. https:\/\/doi.org\/10.1016\/j.bbamem.2014.11.004 (2015).","journal-title":"Biochim. Biophys. Acta"},{"issue":"7","key":"92951_CR29","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1007\/s00249-016-1136-z","volume":"45","author":"B Stegen","year":"2016","unstructured":"Stegen, B. et al. K+ channel signaling in irradiated tumor cells. Eur. Biophys. J. 45(7), 585\u2013598. https:\/\/doi.org\/10.1007\/s00249-016-1136-z (2016).","journal-title":"Eur. Biophys. J."},{"issue":"1","key":"92951_CR30","doi-asserted-by":"publisher","first-page":"a002576","DOI":"10.1101\/cshperspect.a002576","volume":"1","author":"DA Goodenough","year":"2009","unstructured":"Goodenough, D. A. & Paul, D. L. Gap junctions. Cold Spring Harb. Perspect. Biol. 1(1), a002576. https:\/\/doi.org\/10.1101\/cshperspect.a002576 (2009).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"92951_CR31","doi-asserted-by":"publisher","first-page":"052412","DOI":"10.1103\/PhysRevE.102.052412","volume":"102","author":"J Cervera","year":"2020","unstructured":"Cervera, J., Ramirez, P. & Levin, M. Community effects allow bioelectrical reprogramming of cell membrane potentials in multicellular aggregates: Model simulations. Phys. Rev. E 102, 052412. https:\/\/doi.org\/10.1103\/PhysRevE.102.052412 (2020).","journal-title":"Phys. Rev. E"},{"key":"92951_CR32","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1002\/bies.201100025","volume":"33","author":"AM Soto","year":"2011","unstructured":"Soto, A. M. & Sonnenschein, C. The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory. Bioessays 33, 332\u2013340. https:\/\/doi.org\/10.1002\/bies.201100025 (2011).","journal-title":"Bioessays"},{"issue":"4","key":"92951_CR33","doi-asserted-by":"publisher","first-page":"e3000670","DOI":"10.1371\/journal.pbio.3000670","volume":"18","author":"C Sonnenschein","year":"2020","unstructured":"Sonnenschein, C. & Soto, A. M. Over a century of cancer research: Inconvenient truths and promising leads. PLoS Biol. 18(4), e3000670. https:\/\/doi.org\/10.1371\/journal.pbio.3000670 (2020).","journal-title":"PLoS Biol."},{"key":"92951_CR34","doi-asserted-by":"publisher","first-page":"541","DOI":"10.3389\/fonc.2020.00541","volume":"10","author":"J Carvalho","year":"2020","unstructured":"Carvalho, J. Cell reversal from a differentiated to a stem-like state at cancer initiation. Front. Oncol. 10, 541. https:\/\/doi.org\/10.3389\/fonc.2020.00541 (2020).","journal-title":"Front. Oncol."},{"key":"92951_CR35","doi-asserted-by":"publisher","first-page":"3835","DOI":"10.1091\/mbc.e13-12-0708","volume":"25","author":"M Levin","year":"2014","unstructured":"Levin, M. Molecular bioelectricity: How endogenous voltage potentials control cell behavior and instruct pattern regulation in vivo. Mol. Biol. Cell. 25, 3835\u20133850. https:\/\/doi.org\/10.1091\/mbc.e13-12-0708 (2014).","journal-title":"Mol. Biol. Cell."},{"key":"92951_CR36","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1002\/ijc.21088","volume":"116","author":"E Papp-Szab\u00f3","year":"2005","unstructured":"Papp-Szab\u00f3, E., Josephy, P. D. & Coomber, B. L. Microenvironmental influences on mutagenesis in mammary epithelial cells. Int. J. Cancer 116, 679\u2013685. https:\/\/doi.org\/10.1002\/ijc.21088 (2005).","journal-title":"Int. J. Cancer"},{"issue":"3 Suppl 1","key":"92951_CR37","doi-asserted-by":"publisher","first-page":"S7","DOI":"10.1016\/j.amepre.2013.10.029","volume":"46","author":"MC White","year":"2014","unstructured":"White, M. C. et al. Age and cancer risk: A potentially modifiable relationship. Am. J. Prev. Med. 46(3 Suppl 1), S7\u2013S15. https:\/\/doi.org\/10.1016\/j.amepre.2013.10.029 (2014).","journal-title":"Am. J. Prev. Med."},{"key":"92951_CR38","doi-asserted-by":"publisher","unstructured":"Peters, M. J., Stinstra, J. G. & Leveles, I. The electrical conductivity of living tissue: A parameter in the bioelectrical inverse problem. In Modeling and Imaging of Bioelectrical Activity. Bioelectric Engineering  (ed. He, B.) https:\/\/doi.org\/10.1007\/978-0-387-49963-5_9 (Springer, 2004).","DOI":"10.1007\/978-0-387-49963-5_9"},{"key":"92951_CR39","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/j.isci.2019.11.023","volume":"22","author":"M Levin","year":"2019","unstructured":"Levin, M., Selberg, J. & Rolandi, M. Endogenous bioelectrics in development, cancer, and regeneration: Drugs and bioelectronic devices as electroceuticals for regenerative medicine. iScience 22, 519\u2013533. https:\/\/doi.org\/10.1016\/j.isci.2019.11.023 (2019).","journal-title":"iScience"},{"key":"92951_CR40","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1089\/ten.tea.2012.0425.rev","volume":"19","author":"S Sundelacruz","year":"2013","unstructured":"Sundelacruz, S., Levin, M. & Kaplan, D. L. Depolarization alters phenotype, maintains plasticity of predifferentiated mesenchymal stem cells. Tissue. Eng. A 19, 1889\u20131908. https:\/\/doi.org\/10.1089\/ten.tea.2012.0425.rev (2013).","journal-title":"Tissue. Eng. A"},{"key":"92951_CR41","doi-asserted-by":"publisher","first-page":"35201","DOI":"10.1038\/srep35201","volume":"6","author":"J Cervera","year":"2016","unstructured":"Cervera, J., Meseguer, S. & Mafe, S. The interplay between genetic and bioelectrical signaling permits a spatial regionalisation of membrane potentials in model multicellular ensembles. Sci. Rep. 6, 35201. https:\/\/doi.org\/10.1038\/srep35201 (2016).","journal-title":"Sci. Rep."},{"issue":"10","key":"92951_CR42","doi-asserted-by":"publisher","first-page":"13567","DOI":"10.1021\/acsomega.8b01514","volume":"3","author":"J Cervera","year":"2018","unstructured":"Cervera, J., Meseguer, S. & Mafe, S. Intercellular connectivity and multicellular bioelectric oscillations in nonexcitable cells: A biophysical model. ACS Omega 3(10), 13567\u201313575. https:\/\/doi.org\/10.1021\/acsomega.8b01514 (2018).","journal-title":"ACS Omega"},{"key":"92951_CR43","doi-asserted-by":"publisher","unstructured":"Glen, C. M., McDevitt, T. C. & Kemp, M. L. Dynamic intercellular transport modulates the spatial patterning of differentiation during early neural commitment. Nat. Commun. 9, 4111. https:\/\/doi.org\/10.1038\/s41467-018-06693-1 (2018).","DOI":"10.1038\/s41467-018-06693-1"},{"key":"92951_CR44","doi-asserted-by":"publisher","unstructured":"Griffeath, D. Self-organization of random cellular automata: Four snapshots. In  Probability and Phase Transition. NATO ASI Series (Series C: Mathematical and Physical Sciences), Vol. 420.  (ed. Grimmett, G.)  https:\/\/doi.org\/10.1007\/978-94-015-8326-8_4 (Springer, 1994).","DOI":"10.1007\/978-94-015-8326-8_4"},{"issue":"12","key":"92951_CR45","doi-asserted-by":"publisher","first-page":"1979","DOI":"10.1002\/jor.22172","volume":"30","author":"DC Genetos","year":"2012","unstructured":"Genetos, D. C., Zhou, Z., Li, Z. & Donahue, H. J. Age-related changes in gap junctional intercellular communication in osteoblastic cells. J. Orthop. Res. 30(12), 1979\u20131984. https:\/\/doi.org\/10.1002\/jor.22172 (2012).","journal-title":"J. Orthop. Res."},{"issue":"6","key":"92951_CR46","doi-asserted-by":"publisher","first-page":"858","DOI":"10.3390\/cancers11060858","volume":"11","author":"AL Potthoff","year":"2019","unstructured":"Potthoff, A. L. et al. Inhibition of gap junctions sensitizes primary glioblastoma cells for temozolomide. Cancers 11(6), 858. https:\/\/doi.org\/10.3390\/cancers11060858 (2019).","journal-title":"Cancers"},{"key":"92951_CR47","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.exger.2003.10.010","volume":"39","author":"U Del Monte","year":"2004","unstructured":"Del Monte, U. & Statuto, M. Drop of connexins: A possible link between aging and cancer?. Exper. Geront. 39, 273\u20135. https:\/\/doi.org\/10.1016\/j.exger.2003.10.010 (2004).","journal-title":"Exper. Geront."},{"key":"92951_CR48","doi-asserted-by":"publisher","first-page":"16105","DOI":"10.1038\/cddiscovery.2016.105","volume":"3","author":"P Wang","year":"2017","unstructured":"Wang, P., Wan, W. W., Xiong, S. L., Feng, H. & Wu, N. Cancer stem-like cells can be induced through dedifferentiation under hypoxic conditions in glioma, hepatoma and lung cancer. Cell Death Discov. 3, 16105. https:\/\/doi.org\/10.1038\/cddiscovery.2016.105 (2017).","journal-title":"Cell Death Discov."},{"key":"92951_CR49","doi-asserted-by":"publisher","first-page":"404","DOI":"10.3389\/fnins.2020.00404","volume":"14","author":"M Ribeiro","year":"2020","unstructured":"Ribeiro, M. et al. Human breast cancer cells demonstrate electrical excitability. Front. Neurosci. 14, 404. https:\/\/doi.org\/10.3389\/fnins.2020.00404 (2020).","journal-title":"Front. Neurosci."},{"key":"92951_CR50","doi-asserted-by":"publisher","first-page":"968","DOI":"10.3389\/fphar.2020.00968","volume":"11","author":"S Tajada","year":"2020","unstructured":"Tajada, S. & Villalobos, C. Calcium permeable channels in cancer hallmarks. Front. Pharmacol. 11, 968. https:\/\/doi.org\/10.3389\/fphar.2020.00968 (2020).","journal-title":"Front. Pharmacol."},{"key":"92951_CR51","doi-asserted-by":"publisher","first-page":"3941","DOI":"10.1038\/s41467-018-06514-510.1038\/s41467-018-06514-5","volume":"9","author":"Q Jiang","year":"2018","unstructured":"Jiang, Q. et al. Identification of small-molecule ion channel modulators in C. elegans channelopathy models. Nat. Commun. 9, 3941. https:\/\/doi.org\/10.1038\/s41467-018-06514-510.1038\/s41467-018-06514-5 (2018).","journal-title":"Nat. Commun."},{"issue":"8","key":"92951_CR52","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1111\/jcmm.12088","volume":"17","author":"ML Pall","year":"2013","unstructured":"Pall, M. L. Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects. J. Cell. Mol. Med. 17(8), 958\u201365. https:\/\/doi.org\/10.1111\/jcmm.12088 (2013).","journal-title":"J. Cell. Mol. Med."},{"issue":"4","key":"92951_CR53","doi-asserted-by":"publisher","first-page":"e0124136","DOI":"10.1371\/journal.pone.0124136","volume":"10","author":"CA Buckner","year":"2015","unstructured":"Buckner, C. A. et al. Inhibition of cancer cell growth by exposure to a specific time-varying electromagnetic field involves T-type calcium channels. PLoS One 10(4), e0124136. https:\/\/doi.org\/10.1371\/journal.pone.0124136 (2015).","journal-title":"PLoS One"},{"issue":"10","key":"92951_CR54","doi-asserted-by":"publisher","first-page":"2040","DOI":"10.1016\/j.bbamem.2017.07.004","volume":"1859","author":"RC Burke","year":"2017","unstructured":"Burke, R. C. et al. Nanosecond pulsed electric fields depolarize transmembrane potential via voltage-gated K+, Ca2+ and TRPM8 channels in U87 glioblastoma cells. Biochim. Biophys. Acta Biomembr. 1859(10), 2040\u20132050. https:\/\/doi.org\/10.1016\/j.bbamem.2017.07.004 (2017).","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"92951_CR55","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.4172\/2324-9110.S1-002","volume":"1","author":"B Chernet","year":"2013","unstructured":"Chernet, B. & Levin, M. Endogenous voltage potentials and the microenvironment: Bioelectric signals that reveal, induce and normalize cancer. J. Clin. Exp. Oncol. Suppl 1, S1-002. https:\/\/doi.org\/10.4172\/2324-9110.S1-002 (2013).","journal-title":"J. Clin. Exp. Oncol. Suppl"},{"issue":"4","key":"92951_CR56","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1016\/j.cell.2017.01.002","volume":"168","author":"A Tubbs","year":"2017","unstructured":"Tubbs, A. & Nussenzweig, A. Endogenous DNA damage as a source of genomic instability in cancer. Cell 168(4), 644\u2013656. https:\/\/doi.org\/10.1016\/j.cell.2017.01.002 (2017).","journal-title":"Cell"},{"key":"92951_CR57","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2018\/3829768","volume":"3829768","author":"YS Sun","year":"2018","unstructured":"Sun, Y. S. Direct-current electric field distribution in the brain for tumor treating field applications: A simulation study. Comput. Math. Methods Med. 3829768, 1\u201313. https:\/\/doi.org\/10.1155\/2018\/3829768 (2018).","journal-title":"Comput. Math. Methods Med."},{"issue":"1","key":"92951_CR58","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.pbiomolbio.2016.07.006","volume":"122","author":"AM Soto","year":"2016","unstructured":"Soto, A. M. et al. Toward a theory of organisms: Three founding principles in search of a useful integration. Prog. Biophys. Mol. Biol. 122(1), 77\u201382. https:\/\/doi.org\/10.1016\/j.pbiomolbio.2016.07.006 (2016).","journal-title":"Prog. Biophys. Mol. Biol."},{"issue":"5","key":"92951_CR59","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1007\/s12038-015-9574-9","volume":"40","author":"G Longo","year":"2015","unstructured":"Longo, G., Montevil, M., Sonnenschein, C. & Soto, A. M. In search of principles for a theory of organisms. J. Biosci. 40(5), 955\u201368. https:\/\/doi.org\/10.1007\/s12038-015-9574-9 (2015).","journal-title":"J. Biosci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92951-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92951-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92951-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T10:26:57Z","timestamp":1670063217000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92951-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,30]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["92951"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-92951-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,30]]},"assertion":[{"value":"21 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The author declares no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"13607"}}