Modeling of pH regulation in tumor cells: Direct interaction between proton-coupled lactate transporters and cancer-associated carbonic anhydrase

Math Biosci Eng. 2018 Dec 13;16(1):320-337. doi: 10.3934/mbe.2019016.

Abstract

The most aggressive tumor cells, which often reside in a hypoxic environment, can release vast amounts of lactate and protons via monocarboxylate transporters (MCTs). This additional proton efflux exacerbates extracellular acidification and supports the formation of a hostile environment. In the present study we propose a novel, data-based model for this proton-coupled lactate transport in cancer cells. The mathematical settings involve systems coupling nonlinear ordinary and stochastic differential equations describing the dynamics of intra- and extracellular proton and lactate concentrations. The data involve time series of intracellular proton concentrations of normoxic and hypoxic MCF-7 breast cancer cells. The good agreement of our final model with the data suggests the existence of proton pools near the cell membrane, which can be controlled by intracellular and extracellular carbonic anhydrases to drive proton-coupled lactate transport across the plasma membrane of hypoxic cancer cells.

Keywords: dynamic buffer capacity; numerical simulations; stochastic differential equations; two-compartment model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport
  • Carbonic Anhydrases / metabolism*
  • Computer Simulation
  • Humans
  • Hydrogen-Ion Concentration
  • Lactates / metabolism*
  • MCF-7 Cells
  • Models, Theoretical
  • Monocarboxylic Acid Transporters / metabolism
  • Muscle Proteins / metabolism
  • Neoplasms / metabolism*
  • Protons
  • Symporters / metabolism

Substances

  • Lactates
  • Monocarboxylic Acid Transporters
  • Muscle Proteins
  • Protons
  • SLC16A3 protein, human
  • SLC16A4 protein, human
  • SLC16A7 protein, human
  • Symporters
  • monocarboxylate transport protein 1
  • Carbonic Anhydrases