Journal
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
Volume 369, Issue 1638, Pages -Publisher
ROYAL SOC
DOI: 10.1098/rstb.2013.0099
Keywords
pH regulation; pH sensing; buffering; carbonic anhydrase; diffusion
Categories
Funding
- Royal Society
- Association for International Cancer Research
- European Union
- British Heart Foundation
- Cancer Research UK
- British Heart Foundation [RG/08/016/26423] Funding Source: researchfish
- Cancer Research UK [11359] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10163] Funding Source: researchfish
- Worldwide Cancer Research [12-0027] Funding Source: researchfish
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Cell survival is conditional on the maintenance of a favourable acid-base balance (pH). Owing to intensive respiratory CO2 and lactic acid production, cancer cells are exposed continuously to large acid-base fluxes, which would disturb pH if uncorrected. The large cellular reservoir of H+-binding sites can buffer pH changes but, on its own, is inadequate to regulate intracellular pH. To stabilize intracellular pH at a favourable level, cells control trans-membrane traffic of H+-ions (or their chemical equivalents, e. g. HCO3-) using specialized transporter proteins sensitive to pH. In poorly perfused tumours, additional diffusion-reaction mechanisms, involving carbonic anhydrase (CA) enzymes, fine-tune control extracellular pH. The ability of H+-ions to change the ionization state of proteins underlies the exquisite pH sensitivity of cellular behaviour, including key processes in cancer formation and metastasis (proliferation, cell cycle, transformation, migration). Elevated metabolism, weakened cell-to-capillary diffusive coupling, and adaptations involving H+/H+-equivalent transporters and extracellular-facing CAs give cancer cells the means to manipulate micro-environmental acidity, a cancer hallmark. Through genetic instability, the cellular apparatus for regulating and sensing pH is able to adapt to extracellular acidity, driving disease progression. The therapeutic potential of disturbing this sequence by targeting H+/H+-equivalent transporters, buffering or CAs is being investigated, using monoclonal antibodies and small-molecule inhibitors.
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