The chemistry, physiology and pathology of pH in cancer

Pawel Swietach

Richard Vaughan-Jones

Adrian Harris

Alzbeta Hulikova

^{Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK}

^{Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK}

e-mail: ku.ca.xo.gapd@hcateiws.lewap

One contribution of 17 to a Theme Issue ‘Ion channels, transporters and cancer’.

Abstract

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.} An external file that holds a picture, illustration, etc.
Object name is rstb20130099-i1.jpg ) 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.}

Keywords: pH regulation, pH sensing, buffering, carbonic anhydrase, diffusion

Abstract

Acknowledgements

The authors acknowledge Jian Ping Jen for assistance in performing experiments on T47D spheroid.

Acknowledgements

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