The Bioelectric Code: Reprogramming Cancer and Aging From the Interface of Mechanical and Chemical Microenvironments

Abstract

Cancer is a complex, heterogeneous group of diseases that can develop through many routes. Broad treatments such as chemotherapy destroy healthy cells in addition to cancerous ones, but more refined strategies that target specific pathways are usually only effective for a limited number of cancer types. This is largely due to the multitude of physiological variables that differ between cells and their surroundings. It is therefore important to understand how nature coordinates these variables into concerted regulation of growth at the tissue scale. The cellular microenvironment might then be manipulated to drive cells toward a desired outcome at the tissue level. One unexpected parameter, cellular membrane voltage (Vm), has been documented to exert control over cellular behavior both in culture and in vivo. Manipulating this fundamental cellular property influences a remarkable array of organism-wide patterning events, producing striking outcomes in both tumorigenesis as well as regeneration. These studies suggest that Vm is not only a key intrinsic cellular property, but also an integral part of the microenvironment that acts in both space and time to guide cellular behavior. As a result, there is considerable interest in manipulating Vm both to treat cancer as well as to regenerate organs damaged or deteriorated during aging. However, such manipulations have produced conflicting outcomes experimentally, which poses a substantial barrier to understanding the fundamentals of bioelectrical reprogramming. Here, we summarize these inconsistencies and discuss how the mechanical microenvironment may impact bioelectric regulation.

Keywords: bioelectricity; mechanical stress; mechanotransduction; morphodynamics; morphogenesis.

Figure 1

The value of Vm in a given cell is determined by the intra- and extracellular concentrations of all ion species present (predominantly Na⁺, K⁺, and Cl⁻) according to the Hodgkin-Katz-Goldman equation (Binggeli and Weinstein, 1986). Changes to Vm can propagate between neighboring cells via ion exchange through gap junctions, or local voltage gating of ion channels (Levin, 2014). This results in gradients of physiological electric charge within the tissue, referred to as the bioelectric field. For example, a wound creates a depolarized front of migrating cells (Chifflet et al., 2005), acting as a break in the tissue-wide bioelectric circuit.

Figure 2

A breadth of factors may impact Vm in vivo. All of these factors change not only throughout space (morphogen gradients, mechanical signals) but also over time during growth processes (development, cell cycle, organ regeneration, tumor formation, aging).

Figure 3

Mechanical and chemical signals present in the cell and surrounding microenvironment are highly interconnected. Altering one variable within this picture could potentially change many factors impacting Vm.