Regulation of tumor pH and the role of carbonic anhydrase 9

Swietach, Pawel; Vaughan-Jones, Richard D.; Harris, Adrian L.

doi:10.1007/s10555-007-9064-0

Cited by 539Enzyme function and inhibitionCancer, Hypoxia, and MetabolismCancer and biochemical research

Regulation of tumor pH and the role of carbonic anhydrase 9

Swietach, Pawel, Vaughan-Jones, Richard D., Harris, Adrian L.·2007·Cancer and Metastasis Reviews

DOI 10.1007/s10555-007-9064-0

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Abstract

The high metabolic rate required for tumor growth often leads to hypoxia in poorly-perfused regions. Hypoxia activates a complex gene expression program, mediated by hypoxia inducible factor 1 (HIF1alpha). One of the consequences of HIF1alpha activation is up-regulation of glycolysis and hence the production of lactic acid. In addition to the lactic acid-output, intracellular titration of acid with bicarbonate and the engagement of the pentose phosphate shunt release CO(2) from cells. Expression of the enzyme carbonic anhydrase 9 on the tumor cell surface catalyses the extracellular trapping of acid by hydrating cell-generated CO(2) into [see text] and H(+). These mechanisms contribute towards an acidic extracellular milieu favoring tumor growth, invasion and development. The lactic acid released by tumor cells is further metabolized by the tumor stroma. Low extracellular pH may adversely affect the intracellular milieu, possibly triggering apoptosis. Therefore, primary and secondary active transporters operate in the tumor cell membrane to protect the cytosol from acidosis. We review mechanisms regulating tumor intracellular and extracellular pH, with a focus on carbonic anhydrase 9. We also review recent evidence that may suggest a role for CA9 in coordinating pH(i) among cells of large, unvascularized cell-clusters.

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CO2 produced by mitochondrial decarboxylation diffuses out of cells and is converted by extracellular carbonic anhydrases into H+ and HCO3−, contributing to extracellular acidification.
“In addition, the surplus of CO2 generated in mitochondrial decarboxylation reactions contributes to the extracellular acidification as well. To this end, CO2 diffuses into the extracellular space, where it becomes converted to H+ and HCO3− by a class of extracellular carbonic anhydrases (Swietach et al., 2007).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Swietach et al., 2007
Intra-tumor acidosis pH is a common feature of many tumors.
“It is now well known that intra tumor acidosis pH is a common feature of many tumors [260, 261].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [261]

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Authors: Swietach, P., Vaughan-Jones, R. D., & Harris, A. L.
Affiliations: University of Oxford (GB)
John Radcliffe Hospital (GB)
Corresponding author: Harris, Adrian L.
ORCID: Swietach, Pawel
Harris, Adrian L.
Venue: Cancer and Metastasis Reviews
Publisher: Springer Science and Business Media LLC
Published: 2007-04-06
Volume: 26
Issue: 2
Pages: 299-310
ISSN: 0167-7659 (ISSN-L)
1573-7233
DOI: 10.1007/s10555-007-9064-0
OpenAlex: W2061184351
Cited by: 539
References: 106
Citations by year: 2026: 13 · 2025: 11 · 2024: 23 · 2023: 16 · 2022: 26 · 2021: 26 · 2020: 30 · 2019: 29 · 2018: 33 · 2017: 29 · 2016: 35 · 2015: 25 · 2014: 36 · 2013: 40 · 2012: 36
FWCI: 2.36
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Cancer and Metastasis Reviews (publishedVersion)
PubMed (publishedVersion)
Funders: Cancer Research UK
British Heart Foundation
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
Keywords: tumor pH, carbonic anhydrase IX, extracellular acidification, tumor hypoxia, hypoxia-inducible factor-1α, glycolysis, lactic acid, bicarbonate, pentose phosphate pathway, tumor stroma, proton transporters, intracellular acidosis, tumor cell clusters, tumor microenvironment
MeSH terms: Carbonic Anhydrase IX, Antigens, Neoplasm, Bicarbonates, Carbon Dioxide, Carbonic Anhydrases, Humans, Hydrogen-Ion Concentration, Models, Biological, Neoplasms, Reference Values, Hypoxia-Inducible Factor 1, alpha Subunit

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