This is important because the acidic pH e can be tolerated by tumour cells but it inhibits growth of normal host cells, thus facilitating invasion and metastasis. We report the first direct in vivo observation of the isoenzyme carbonic anhydrase IX (CAIX) acting as a pH-stat that sets the extracellular pH (pH e) of solid tumours at an acidic level. 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. 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.ConclusionsCAIX acidifies the tumour microenvironment, and also provides an extracellular pH control mechanism. Importantly, CAIX expression imposed an upper limit for tumour extracellular pH at 6.93.
We also measured intracellular pH in situ with 31P MRS and measured lactate in freeze-clamped tumours.ResultsCAIX-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).
BackgroundTumour 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.MethodsWe 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.
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