Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo
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Authors
Griffiths, John Richard
Lee, Shen-Han
Honess, Davina
Hulikova, Alzbeta
Pacheco-Torres, Jesus
Cerdan, Sebastian
Harris, Adrian L
Publication Date
2018-08Journal Title
British Journal of Cancer
ISSN
1532-1827
Publisher
Springer Nature
Volume
119
Pages
622-630
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Griffiths, J. R., Lee, S., McIntyre, D., Honess, D., Hulikova, A., Pacheco-Torres, J., Cerdan, S., & et al. (2018). Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo. British Journal of Cancer, 119 622-630. https://doi.org/10.1038/s41416-018-0216-5
Abstract
Background
Tumour Carbonic Anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, is thought to acidify the tumour microenvironment by hydrating CO2 to form protons and bicarbonate, but there is no definitive evidence for this in solid tumours in vivo.
Methods
We used 1H magnetic resonance spectroscopic imaging (MRSI) of the extracellular pH probe imidazolyl succinic acid (ISUCA) to measure and spatially map extracellular pH in HCT116 tumours transfected to express CAIX and empty vector controls in SCID mice. We also measured intracellular pH in situ with 31P MRS and measured lactate in freeze-clamped tumours.
Results
CAIX expressing tumours had 0.15 pH-unit lower median extracellular pH than control tumours (pH 6.71 tumour vs pH 6.86 control, P = 0.01). Importantly, CAIX expression imposed an upper limit for tumour extracellular pH at 6.93. Despite the increased lactate concentration in CAIX-expressing tumours, 31P MRS showed no difference in intracellular pH, suggesting that CAIX acidifies only the tumour extracellular space.
Conclusions
CAIX acidifies the tumour microenvironment, and also provides an extracellular pH control mechanism. We propose that CAIX thus acts as an extracellular pH-stat, maintaining an acidic tumour extracellular pH that is tolerated by cancer cells and favours invasion and metastasis.
Keywords
carbonic anhydrase IX, tumour pH, extracellular pH, intracellular pH, ISUCA, Magnetic Resonance Spectroscopy, MRS, pH-stat
Sponsorship
We are grateful for the support of CRUK [grant number C14303/A17197], the Breast Cancer Research Foundation, the Royal Society, Worldwide Cancer Research and the European Research Council [SURVIVE: 723397]. JP-T and SC received support from the Spanish Ministry of Economy and Competitiveness SAF2014-23622.
Funder references
Cancer Research UK (CB4110)
Identifiers
External DOI: https://doi.org/10.1038/s41416-018-0216-5
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287141
Rights
Attribution 4.0 International, Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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