The control of acidity in tumor cells: a biophysical model

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 consumptionwithlactateandCO productionandconnectstheseprocessestoH+andHCO−fluxes 2 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 HCO− exchanges in the inner hypoxic regions where tumor cells are 3 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.