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Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo

BACKGROUND: Tumour carbonic anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, is thought to acidify the tumour microenvironment by hydrating CO(2) to form protons and bicarbonate, but there is no definitive evidence for this in solid tumours in vivo. METHODS: We used (1...

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Autores principales: Lee, Shen-Han, McIntyre, Dominick, Honess, Davina, Hulikova, Alzbeta, Pacheco-Torres, Jesús, Cerdán, Sebastián, Swietach, Pawel, Harris, Adrian L., Griffiths, John R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162214/
https://www.ncbi.nlm.nih.gov/pubmed/30206370
http://dx.doi.org/10.1038/s41416-018-0216-5
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author Lee, Shen-Han
McIntyre, Dominick
Honess, Davina
Hulikova, Alzbeta
Pacheco-Torres, Jesús
Cerdán, Sebastián
Swietach, Pawel
Harris, Adrian L.
Griffiths, John R.
author_facet Lee, Shen-Han
McIntyre, Dominick
Honess, Davina
Hulikova, Alzbeta
Pacheco-Torres, Jesús
Cerdán, Sebastián
Swietach, Pawel
Harris, Adrian L.
Griffiths, John R.
author_sort Lee, Shen-Han
collection PubMed
description BACKGROUND: Tumour carbonic anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, is thought to acidify the tumour microenvironment by hydrating CO(2) to form protons and bicarbonate, but there is no definitive evidence for this in solid tumours in vivo. METHODS: We used (1)H 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 (31)P 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, (31)P 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.
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spelling pubmed-61622142019-09-04 Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo Lee, Shen-Han McIntyre, Dominick Honess, Davina Hulikova, Alzbeta Pacheco-Torres, Jesús Cerdán, Sebastián Swietach, Pawel Harris, Adrian L. Griffiths, John R. Br J Cancer Article BACKGROUND: Tumour carbonic anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, is thought to acidify the tumour microenvironment by hydrating CO(2) to form protons and bicarbonate, but there is no definitive evidence for this in solid tumours in vivo. METHODS: We used (1)H 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 (31)P 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, (31)P 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. Nature Publishing Group UK 2018-09-12 2018-08-28 /pmc/articles/PMC6162214/ /pubmed/30206370 http://dx.doi.org/10.1038/s41416-018-0216-5 Text en © The Author(s) 2018 https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Lee, Shen-Han
McIntyre, Dominick
Honess, Davina
Hulikova, Alzbeta
Pacheco-Torres, Jesús
Cerdán, Sebastián
Swietach, Pawel
Harris, Adrian L.
Griffiths, John R.
Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo
title Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo
title_full Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo
title_fullStr Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo
title_full_unstemmed Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo
title_short Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo
title_sort carbonic anhydrase ix is a ph-stat that sets an acidic tumour extracellular ph in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162214/
https://www.ncbi.nlm.nih.gov/pubmed/30206370
http://dx.doi.org/10.1038/s41416-018-0216-5
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