The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion

Abstract

A number of studies have shown that the extracellular pH (pHe) in cancers is typically lower than that in normal tissue and that an acidic pHe promotes invasive tumor growth in primary and metastatic cancers. Here, we investigate the hypothesis that increased systemic concentrations of pH buffers reduce intratumoral and peritumoral acidosis and, as a result, inhibit malignant growth. Computer simulations are used to quantify the ability of systemic pH buffers to increase the acidic pHe of tumors in vivo and investigate the chemical specifications of an optimal buffer for such purpose. We show that increased serum concentrations of the sodium bicarbonate (NaHCO(3)) can be achieved by ingesting amounts that have been used in published clinical trials. Furthermore, we find that consequent reduction of tumor acid concentrations significantly reduces tumor growth and invasion without altering the pH of blood or normal tissues. The simulations also show that the critical parameter governing buffer effectiveness is its pK(a). This indicates that NaHCO(3), with a pK(a) of 6.1, is not an ideal intratumoral buffer and that greater intratumoral pHe changes could be obtained using a buffer with a pK(a) of approximately 7. The simulations support the hypothesis that systemic pH buffers can be used to increase the tumor pHe and inhibit tumor invasion.

Figure 1

Tumor microenvironment. An avascular tumor with regions of hypoxia and anoxia produces both carbon dioxide from respiration and protons from anaerobic glycolysis. Bicarbonate buffers the pHe in the tissue by converting protons into water and carbon dioxide; the latter diffuses back to blood vessels and is expelled in the lungs.

Figure 2

TSim graphical user interface view of the tumor model. Blue, one eighth of the tumor sphere. Pink, healthy tissue perfused by blood vessels (red). Simulations allow tumor growth to be simulated along with regional variations in pHe, as well as O₂, CO₂, and glucose concentrations and intracellular ATP.

Figure 3

For each volume in simulation space at time t, the diffusion, metabolism, cell duplication, and death are calculated and the updated model is stored in the respective volume at time t + 1. Diffusion is calculated through an approximate algorithm with steps of one tenth of a second. Each generation of the simulation is composed of 50 metabolic steps, after which the decision is made on cell fate: duplication, death, or remain as is.

Figure 4

A, the effects of increased serum bicarbonate concentration on pHe gradient in tumors with 100-fold increase in glucose metabolism. B, the dependency of pHe gradient on the diffusion rate of a hypothetical buffer added to serum. C, the pHe gradient produced by a hypothetical non–CO₂-producing buffer compared with bicarbonate confirms that no noticeable difference exists if the other chemical properties (i.e., pK) are kept equal for the two buffers.

Figure 5

Dependency of pHe gradient on the value of the pK_a of the hypothetical buffer and comparison with no treatment. Inset, pHe increase (in pH units) in tumor center and tumor rim.

Figure 6

pHe distributions in and around tumors along with tumor growth after 20 generations with normal (top row) serum bicarbonate and with a 40% increase in concentration. As outlined in the text, pHe was much less acidic in the presence of increased serum buffer, resulting in a dramatic reduction in tumor invasion.