Introduction
In recent years, an overwhelming amount of interest in the pH dysregulation of cancer cells has surfaced. While the term ‘cancer’ defines a wide variety of diseases, it is recognized that all cancers share basic adaptive characteristics that differentiate them from normal cells and contribute to the cancerous phenotype, such as an increase in glycolytic metabolism\cite{Gatenby_2004} and a decrease in oxidative phosphorylation\cite{Dey_2000,Grippo_2017}. This metabolic shift in cancer, termed the “Warburg Effect”, is often accompanied by cellular changes in redox\cite{Jorgenson_2013,Moreira_2016}, osmolarity\cite{Counillon_2016}, mitochondrial membrane potential\cite{Dey_2000}, and dysregulated pH\cite{Schwartz_2017,Webb_2011}. Specifically, the pH gradient between the cytosol and the extracellular space is reversed in cancers, with cancer cells having an increased pHi (7.3-7.6 versus 7.2 in normal cells) and decreased pHe (6.8-7.0 versus 7.4 in normal cells)\cite{White_2017}. This pH gradient reversal is now recognized as a critically important hallmark of cancer.
In cancer cells, the pHi increases while the pHe decreases as a result of upregulation of ion transporters such as the Na+-H+ exchanger NHE1\cite{Counillon_2016,McLean_2000,Chiang_2007} and monocarboxylate-H+ efflux cotransporters\cite{Pinheiro_2008,Chiche_2011,Damaghi_2013}, which pump protons from the cytosol into the extracellular space (figure 1). Carbonic anhydrases that hydrolyze CO2 into HCO3- and H+ in the extracellular space also contribute to the pH gradient reversal\cite{Swietach_2009,Pastorek_2008}. These pH changes have been found to promote cancerous behaviors, including proliferation, apoptosis evasion, metabolic adaptation, cell migration, and tumorigenesis.