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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-08

AUTHORS

Shen-Han Lee, Dominick McIntyre, Davina Honess, Alzbeta Hulikova, Jesús Pacheco-Torres, Sebastián Cerdán, Pawel Swietach, Adrian L. Harris, John R. Griffiths

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. More... »

PAGES

622-630

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41416-018-0216-5

DOI

http://dx.doi.org/10.1038/s41416-018-0216-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1106909439

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30206370


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