The control of acidity in tumor cells: a biophysical model

Abstract

Acidosis of the tumor microenvironment leads to cancer invasion, progression and resistance to therapies. We present a biophysical model that describes how tumor cells regulate intracellular and extracellular acidity while they grow in a microenvironment characterized by increasing acidity and hypoxia. The model takes into account the dynamic interplay between glucose and O2 consumption with lactate and CO2 production and connects these processes to H+ and [Formula] fluxes inside and outside cells. We have validated the model with independent experimental data and used it to investigate how and to which extent tumor cells can survive in adverse micro-environments characterized by acidity and hypoxia. The simulations show a dominance of the H+ exchanges in well-oxygenated regions, and of [Formula] exchanges in the inner hypoxic regions where tumor cells are known to acquire malignant phenotypes. The model also includes the activity of the enzyme Carbonic Anhydrase 9 (CA9), a known marker of tumor aggressiveness, and the simulations demonstrate that CA9 acts as a nonlinear pHi equalizer at any O2 level in cells that grow in acidic extracellular environments. SIGNIFICANCEThe activity of cancer cells in solid tumors affects the surrounding environment in many ways, and an elevated acidity is a common feature of the tumor microenvironment. In this paper we propose a model of intracellular/extracellular acidity that is linked to cellular metabolism and includes all the main molecular players. The model is reliable, robust and validated with experimental data and can be used as an essential building block of more comprehensive in silico research on solid tumors.