A general reaction-diffusion model of acidity in cancer invasion

We model the metabolism and behaviour of a developing cancer tumour in the context of its microenvironment, with the aim of elucidating the consequences of altered energy metabolism. Of particular interest is the Warburg Effect, a widespread preference in tumours for cytosolic glycolysis rather than oxidative phosphorylation for glucose breakdown, as yet incompletely understood. We examine a candidate explanation for the prevalence of the Warburg Effect in tumours, the acid-mediated invasion hypothesis, by generalising a canonical non-linear reaction–diffusion model of acid-mediated tumour invasion to consider additional biological features of potential importance. We apply both numerical methods and a non-standard asymptotic analysis in a travelling wave framework to obtain an explicit understanding of the range of tumour behaviours produced by the model and how fundamental parameters govern the speed and shape of invading tumour waves. Comparison with conclusions drawn under the original system—a special case of our generalised system—allows us to comment on the structural stability and predictive power of the modelling framework

The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela.

Cancer cells have an unusual regulation of hydrogen ion dynamics that are driven by poor vascularity perfusion, regional hypoxia, and increased glycolysis. All these forces synergize/orchestrate together to create extracellular acidity and intracellular alkalinity. Precisely, they lead to extracellular pH (pHe) values as low as 6.2 and intracellular pH values as high as 8. This unique pH gradient (∆pHi to ∆pHe) across the cell membrane increases as the tumor progresses, and is markedly displaced from the electrochemical equilibrium of protons. These unusual pH dynamics influence cancer cell biology, including proliferation, metastasis, and metabolic adaptation. Warburg metabolism with increased glycolysis, even in the presence of Oxygen with the subsequent reduction in Krebs’ cycle, is a common feature of most cancers. This metabolic reprogramming confers evolutionary advantages to cancer cells by enhancing their resistance to hypoxia, to chemotherapy or radiotherapy, allowing rapid production of biological building blocks that support cellular proliferation, and shielding against damaging mitochondrial free radicals. In this article, we highlight the interconnected roles of dysregulated pH dynamics in cancer initiation, progression, adaptation, and in determining the programming and re-programming of tumor cell metabolism

Glycolysis, Tumor Metabolism, Cancer Growth and Dissemination. A new pH-based Etiopathogenic Perspective and Therapeutic Approach to an old Cancer Question

Cancer cells acquire an unusual glycolytic behavior to a large extent relative to an intracellular alkaline (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 propose a 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