Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question

Abstract

Cancer cells acquire an unusual glycolytic behavior relative, to a large extent, to their intracellular alkaline pH (pHi). This effect is part of the metabolic alterations found in most, if not all, cancer cells to deal with unfavorable conditions, mainly hypoxia and low nutrient supply, in order to preserve its evolutionary trajectory with the production of lactate after ten steps of glycolysis. Thus, cancer cells reprogram their cellular metabolism in a way that gives them their evolutionary and thermodynamic advantage. Tumors exist within a highly heterogeneous microenvironment and cancer cells survive within any of the different habitats that lie within tumors thanks to the overexpression of different membrane-bound proton transporters. This creates a highly abnormal and selective proton reversal in cancer cells and tissues that is involved in local cancer growth and in the metastatic process. Because of this environmental heterogeneity, cancer cells within one part of the tumor may have a different genotype and phenotype than within another part. This phenomenon has frustrated the potential of single-target therapy of this type of reductionist therapeutic approach over the last decades. Here, we present a detailed biochemical framework on every step of tumor glycolysis and then proposea new paradigm and therapeutic strategy based upon the dynamics of the hydrogen ion in cancer cells and tissues in order to overcome the old paradigm of one enzyme-one target approach to cancer treatment. Finally, a new and integral explanation of the Warburg effect is advanced.

Keywords: Tumor glycolysis; cancer growth; cancer treatment; metastatic process; new paradigm in oncology; pH and cancer; pH and glycolysis; proton transport inhibitors.

Figure 1. Conversion of Glucose into Glucose – 6 – Phosphate

Figure 2. Shows isomerization of Glucose-6-phosphate into fructose-6-phosphate

Figure 3. Shows phosphorylation of Fructose – 6-Phosphate into Fructose – 1, 6 – biphosphate

Figure 4. hydrolysis of Fructose – 1, 6 – biphosphate into D-glyceraldehyde 3-phosphate (GADP) and Dihydroxyacetone phosphate (DHAP)

Figure 5. conversion of D-glyceraldehyde 3-phosphate (GADP) into into 1, 3-bisphosphoglycerate

Figure 6. conversion of 1, 3 - bisphosphoglycerate into 3-phosphoglycerate

Figure 7. Shows conversion of into 3-phosphoglycerate into 2-phosphoglycerate

Figure 8. shows conversion of 2-phosphoglycerate into Phosphoenolpyruvate

Figure 9. shows conversion of Phosphoenolpyruvate into Pyruvate