Transmembrane voltage potential of somatic cells controls oncogene-mediated tumorigenesis at long-range

• Published in: Oncotarget Vol. 5; no. 10; pp. 3287 - 3306
• Main Authors: Chernet, Brook T, Levin, Michael
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 30.05.2014
• Subjects: Animals; Carcinogenesis; Embryo, Nonmammalian; Humans; Immunohistochemistry; Membrane Potentials - physiology; Oncogenes - physiology; Research Paper; Tumor Microenvironment - physiology; Xenopus laevis
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.1935

The microenvironment is increasingly recognized as a crucial aspect of cancer. In contrast and complement to the field's focus on biochemical factors and extracellular matrix, we characterize a novel aspect of host:tumor interaction - endogenous bioelectric signals among non-excitable somatic cells. Extending prior work focused on the bioelectric state of cancer cells themselves, we show for the first time that the resting potentials of distant cells are critical for oncogene-dependent tumorigenesis. In the Xenopus laevis tadpole model, we used human oncogenes such as mutant KRAS to drive formation of tumor-like structures that exhibited overproliferation, increased nuclear size, hypoxia, acidity, and leukocyte attraction. Remarkably, misexpression of hyperpolarizing ion channels at distant sites within the tadpole significantly reduced the incidence of these tumors. The suppression of tumorigenesis could also be achieved by hyperpolarization using native CLIC1 chloride channels, suggesting a treatment modality not requiring gene therapy. Using a dominant negative approach, we implicate HDAC1 as the mechanism by which resting potential changes affect downstream cell behaviors. Based on published data on the voltage-mediated changes of butyrate flux through the SLC5A8 transporter, we present a model linking resting potentials of host cells to the ability of oncogenes to initiate tumorigenesis. Antibiotic data suggest that the relevant butyrate is generated by a native bacterial species, identifying a novel link between the microbiome and cancer that is mediated by alterations in bioelectric signaling.