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 hbox {O}_2 consumption with lactate and hbox {CO}_2 production and connects these processes to hbox {H}^+ and hbox {HCO}_3^- 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 hbox {H}^+ exchanges in well-oxygenated regions, and of hbox {HCO}_3^- 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 hbox {pH}_i equalizer at any hbox {O}_2 level in cells that grow in acidic extracellular environments.
Highlights
Acidosis of the tumor microenvironment leads to cancer invasion, progression and resistance to therapies
We study the action of key molecular actors in acid homeostasis of cancer cells, and investigate to which extent hypoxia and environmental acidosis influence their behavior
We start from the rather detailed model of tumor cell metabolism and growth that we developed in our previous r esearch[6,7,8] which successfully reproduces the observed behavior of tumor cells in both liquid and solid tumors
Summary
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. 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. 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. Acid homeostasis in animal tissues is achieved by active dynamic processes. The pH of tissues is maintained between 7.35 and 7.45 in spite of constant metabolic acid production by cells. Cellular acid homeostasis is carried out by active transport of acid/base equivalents across the cell membranes into the extracellular spaces
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
