Cancer as a Channelopathy—Appreciation of Complimentary Pathways Provides a Different Perspective for Developing Treatments

Figure 1. The diagram presents major steps in the metabolic pathways occur in cells in response to extrinsic environmental challenges (hypertonicity, hypoxia, toxins, immune response, and trauma) and intrinsic signaling that trigger influx (+) or efflux (−) of ions orchestrated through numerous channels between the extracellular matrix and the intracellular space resulting in shifts in cell volume, downstream activation, increase (inc), decrease (dec), or inhibition (X) of processes affecting cellular function and survival. The numbers and types of channels expressed and the resulting number of ions exchanged determines cellular functioning and provides targets for developing treatments to modulate pathologic change and provides the means for cells to develop resistance and avoid elimination with intervention affecting steps closer to cellular elimination having less opportunity for resistance.

Figure 2. The illustration depicts important characteristics of normal apoptosis that rely on proper ion channel expression and function and are essential for maintaining healthy organ structure and integrity. The circular profiles represent relative size of normal cells (black circles) and cells scheduled for programmed cell death (red circles). Parallel green bars and yellow dots represent typical ion channels and their restorative mechanisms, here for Na+, respectively. Arrows denote the direction of ionic flow. Dividing cells are indicated by overlapping circles and bold lines. Beginning in (A), normal cells for a portion of functioning organ are rendered with relatively uniform size. As apoptosis begins (B), there is a shift in ion channel function in the cells scheduled for apoptotic death (red circles) resulting in a decrease in volume that progresses through (C,D) as the process continues. This process provides room for replacement cells seen dividing in (D). Upon completion of cell division, the remains of the dead cells are removed by phagocytosis maintaining structural integrity in (A), while renewing component cells. Note that this process occurs without initiating inflammation.

Figure 3. The illustration presents important characteristics of necrosis that distinguish this form of cell death with apoptosis. Conventions are the same as used in Figure 1. There are normal cells in (A). A nidus of injury (small purple circles) and an area of inflammation (shaded area) initiated to control the amount of injury and heal the wound is illustrated in (B). The inflammatory mediators affect a change in channel expression in local cells resulting in an increase in cell volume for normal cells and a maintenance of cell volume in cells scheduled for apoptotic death. In (C), lytic enzymes in the area of inflammation affect lethal changes in the genetic code and initiate necrosis in the previously normal cells (large circles with dashed purple borders). These changes lead to the extension of the area of inflammation and enhance the effect on channel expression and function. Shifts in channel expression and function in response to changes in the extracellular matrix illustrated in (D), support the cells scheduled for apoptosis channel. Increases in Na+ channel expression supports survival and enhances cell motility and the ability to invade to areas beyond the area of inflammation.