The Role of pH Regulation in Cancer Progression
Frequently observed phenotypes of tumours include high metabolic activity, hypoxia and poor perfusion; these act to produce an acidic microenvironment. Cellular function depends on pH homoeostasis, and thus, tumours become dependent on pH regulatory mecha
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Abstract
Frequently observed phenotypes of tumours include high metabolic activity, hypoxia and poor perfusion; these act to produce an acidic microenvironment. Cellular function depends on pH homoeostasis, and thus, tumours become dependent on pH regulatory mechanisms. Many of the proteins involved in pH regulation are highly expressed in tumours, and their expression is often of prognostic significance. The more acidic tumour microenvironment also has important implications with regard to chemotherapeutic and radiotherapeutic interventions. In addition, we review pH-sensing mechanisms, the role of pH regulation in tumour phenotype and the use of pH regulatory mechanisms as therapeutic targets. Keywords
pH regulation Hypoxia microenvironment
Tumour
Carbonic anhydrase 9
acidic
A. McIntyre A.L. Harris (&) Molecular Oncology Laboratories, Department of Medical Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK e-mail: [email protected] © Springer International Publishing Switzerland 2016 T. Cramer and C.A. Schmitt (eds.), Metabolism in Cancer, Recent Results in Cancer Research 207, DOI 10.1007/978-3-319-42118-6_5
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A. McIntyre and A.L. Harris
Introduction
1.1 Measurements of Intracellular and Extracellular Tumour pH For many years, it was rightly assumed that the increased conversion of glucose to lactic acid (the Warburg effect) seen in tumours would result in more acidic tumour microenvironment. It was also assumed that this would result in a more acidic intracellular pH. Indeed, initial measurements of tumour pH using pH electrodes inserted into tumours showed a more acidic pH (range 5.6–7.6) than normal tissues (range 6.9–7.6) (Griffiths 1991). However, the pH probes used in these studies were often large compared to single tumour cells and are now understood to have mostly measured extracellular pH (Griffiths 1991). Tumour pH has been measured by a number of imaging techniques including positron emission tomography (PET), magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) (Zhang et al. 2010). Measurement of pH by 31P-MRS tends to reflect the intracellular pH of tumours which is much more neutral than the extracellular pH in tumour cells (range 6.8–7.4) (Griffiths 1991; Zhang et al. 2010; Gerweck and Seetharaman 1996). In normal tissue, the intracellular pH tends to be more similar to, or more acidic than, the extracellular pH (range 6.8–7.3) (Griffiths 1991; Gerweck and Seetharaman 1996). In addition, the intracellular pH can be more alkaline in tumour cells compared to normal cells; for example, assessment of pH in malignant gliomas revealed a more alkaline steady-state intracellular pH (7.31– 7.48) than was identified in normal astrocytes (6.98) (McLean et al. 2000). Therefore, there is a shift in the intracellular/extracellular balance of pH in tumour cells compared to normal cells, producing at least a reduced gradient and in many cases reversal in pH gradients for cancer cells. This has also been shown exper
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