How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH

Abstract

The acidic tumour microenvironment is now recognized as a tumour phenotype that drives cancer somatic evolution and disease progression, causing cancer cells to become more invasive and to metastasise. This property of solid tumours reflects a complex interplay between cellular carbon metabolism and acid removal that is mediated by cell membrane carbonic anhydrases and various transport proteins, interstitial fluid buffering, and abnormal tumour-associated vessels. In the past two decades, a convergence of advances in the experimental and mathematical modelling of human cancers, as well as non-invasive pH-imaging techniques, has yielded new insights into the physiological mechanisms that govern tumour extracellular pH (pH_e). In this review, we examine the mechanisms by which solid tumours maintain a low pH_e, with a focus on carbonic anhydrase IX (CAIX), a cancer-associated cell surface enzyme. We also review the accumulating evidence that suggest a role for CAIX as a biological pH-stat by which solid tumours stabilize their pH_e. Finally, we highlight the prospects for the clinical translation of CAIX-targeted therapies in oncology.

Keywords: cancer metabolism; cancer microenvironment; carbonic anhydrase IX; magnetic resonance spectroscopy; models of tumour pH regulation; pH measurement in vivo; pH-stat; tumour pH.

Figure 1

Carbonic anhydrase IX (CAIX) links tumour energy metabolism to its pH regulation. 1. The major by-product of oxidative energy metabolism, CO₂ diffuses across the cell membrane lipid bilayer into the extracellular space, along its concentration gradient; 2. On the extracellular surface of the cell membrane, the exofacial catalytic domain of CAIX catalyses the hydration of CO₂ to form H⁺ and HCO₃⁻; 3. In parallel, lactate, the end-product of glycolysis, exits the cell through the monocarboxylate transporter at a rate that is influenced by the pH gradient across the cell membrane (pH_i–pH_e gradient). GLUT, glucose transporter; MCT, monocarboxylate transporter.

Figure 2

A Jacobs–Stewart Cycle helps hypoxic cancer cells extrude H⁺ produced by anaerobic glycolysis. 1. CO₂ diffuses from the cancer cell into the extracellular space; 2. CAIX on the extracellular surface of the hypoxic cancer cell catalyses the hydration of CO₂ to form H⁺ and HCO₃⁻; 3. The HCO₃⁻ enters the hypoxic cancer cell via the Na⁺/HCO₃⁻ cotransporter and binds H⁺ from lactic acid, catalysed by CAII, thus forming CO₂; 4. The CO₂ diffuses from the hypoxic cancer cell into the extracellular space, along its concentration gradient; 5. On the extracellular surface of the hypoxic cancer cell, CAIX catalyses the hydration of the CO₂ to form H⁺ and HCO₃⁻. The HCO₃⁻ provides further substrate to repeat stage 3 of the cycle, and an equivalent amount of H⁺ that was originally inside the hypoxic cancer cell (ringed in red) is now in the extracellular fluid; 6. Accumulating CO₂ diffuses to a capillary. GLUT, glucose transporter; MCT, monocarboxylate transporter; NBC, Na⁺/HCO₃⁻ cotransporter.