Mathematical Modelling of Tumor Acidity: Regulation of Intracellular pH

Measurements of extracelluar pH (pHe)in vivohave shown that the microenvironment in tumors is more acidic than in normal tissue. However, both human and animal tumor cells have been shown to have an intracellular pH (pHi) on the alkaline side of neutrality (pH 7.1–7.2). This gives rise to a reversed pH gradient between tumors and normal tissue which implies that cells within solid tumors are capable of maintaining their level of pHiat physiological levels, despite lower than normal levels of pHe. In this paper the authors describe a mathematical model that provides a possible explanation for the altered pH gradient observed in tumors. The authors examine the influence of changes in the microenvironment on the activity of several membrane based ion transport systems. Using qualitative analysis the authors show that the pHiof tumor cells is less sensitive to external pH than for normal cells, because if their increased reliance on the inefficient glycolytic pathway for energy production. It is shown that under aerobic conditions the lactate−/H+symporter could be the most active exchanger in the regulation of pHiin tumor cells. However, under more hypoxic conditions lactate extrusion is reduced, and so this exchanger has little effect on resting pHiin these regions. The authors also consider an extended model which incorporates the transfer of acids from the cytosol into acidic organelles. The model demonstrates that one of the major factors involved in the maintenance of cytosolic pH to physiological levels, despite an acidic extracellular pH in hypoxic areas of tumor tissue (median, 6.9–7.0), is enhanced sequestration of cytosolic protons into acidic cellular vesicles such as endoplasmic reticulum, golgi, endosomes, and lysosomes.