Membrane voltage and connexin expression work together to enhance tumor growth and metastasis in cancer

There is strong evidence of tumors manipulating their resting membrane potential (Vmem). While most fully-differentiated cells have a Vmem of roughly -70mV, tumor cells are generally depolarized, with Vmem {approx}-30mV, which more closely resembles the Vmem of stem cells. This is often believed to serve the purpose of accelerating the cell cycle and hence advantaging tumor proliferation. But when the tumor becomes invasive, its cells sometimes revert to a hyperpolarized Vmem with no obvious reason why. Separately, it is well accepted that solid tumors that are not yet invasive greatly underexpress connexins relative to healthy tissue; connexins, for our purpose, form gap junctions (GJs), small connecting tubes between nearby cells. Tumors that are invasive, by contrast, overexpress connexins. There is very little explanation for the paradox that connexins are first underexpressed and then overexpressed. However, it has long been known that Vmem electrically gates GJs; specifically, that homotypic GJs conduct best when the two cells they connect have a similar Vmem. Our in-silico model results explain this phenomenon, showing that when considered together, tumors' electrical and connexin-expression behaviors form a unified and effective strategy to control communication between the tumor and its healthy neighbor cells. This has implications for the emerging field of cancer bioelectrics, potentially leading to more precisely-targeted therapies.