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Tumour acidosis: from the passenger to the driver's seat

Key Points

  • In contrast to healthy tissues, the extracellular pH of tumours is generally acidic, while the intracellular pH is slightly alkaline.

  • Exacerbated glycolysis and respiration through hydration of CO2 contribute to the release of H+ ions in the tumour microenvironment, making gradients of acidosis and hypoxia non-overlapping.

  • Tumour acidosis induces a shift from HIF1α-driven glycolytic metabolism towards the metabolism of glutamine and lipids as preferred sources of energy and biosynthetic intermediates.

  • Adaptation of cancer cells to acidosis requires transcriptional (for example, HIF2α induction), post-translational (for example, changes in protein acetylation) and morphological alterations (for example, mitochondria elongation with an increase in cristae numbers).

  • Acidosis-driven tumour progression is promoted by a reduction in immunosurveillance and changes in lysosome biology that support invasiveness and autophagy.

  • Tumour acidosis can be targeted by drugs interfering with H+ or bicarbonate transporters, neutralized by systemic buffer administration or exploited using pH-sensitive drug-delivery systems.

Abstract

The high metabolic demand of cancer cells leads to an accumulation of H+ ions in the tumour microenvironment. The disorganized tumour vasculature prevents an efficient wash-out of H+ ions released into the extracellular medium but also favours the development of tumour hypoxic regions associated with a shift towards glycolytic metabolism. Under hypoxia, the final balance of glycolysis, including breakdown of generated ATP, is the production of lactate and a stoichiometric amount of H+ ions. Another major source of H+ ions results from hydration of CO2 produced in the more oxidative tumour areas. All of these events occur at high rates in tumours to fulfil bioenergetic and biosynthetic needs. This Review summarizes the current understanding of how H+-generating metabolic processes segregate within tumours according to the distance from blood vessels and inversely how ambient acidosis influences tumour metabolism, reducing glycolysis while promoting mitochondrial activity. The Review also presents novel insights supporting the participation of acidosis in cancer progression via stimulation of autophagy and immunosuppression. Finally, recent advances in the different therapeutic modalities aiming to either block pH-regulatory systems or exploit acidosis will be discussed.

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Figure 1: Model depicting the relationship between O2 levels, sources of H+ and venting in a tumour mass and the surrounding microenvironment.
Figure 2: Tumour metabolic adaptation under acidosis.
Figure 3: Consequences of tumour microenvironment acidification on cancer progression.
Figure 4: Therapeutic targets and modalities to manipulate extracellular pH and intracellular pH in tumours.

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Acknowledgements

This work was supported by grants from the Fonds National de la Recherche Scientifique (FRS-FNRS), the Télévie, the Belgian Foundation against Cancer, the J. Maisin Foundation and an Action de Recherche Concertée from the Fédération Wallonie-Bruxelles (ARC 14/19-058). C.C. is a senior FRS-FNRS postdoctoral fellow.

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O.F. and C.C. wrote the article and conceived the figures and other display items. O.F. and C.C. reviewed and edited the article before final submission.

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Glossary

Symporter

An integral membrane protein that mediates the unidirectional co-transport of two molecules across a cell membrane.

Glutaminolysis

The metabolism of glutamine that yields a variety of products, including glutamate, α-ketoglutarate, malate, pyruvate and lactate.

Syncytium

A group of cells coupled by gap junction-mediated connections.

Metabolic symbiosis

A biological cooperation between two cell populations, one consuming a metabolite that is produced by the other, which in turn derives growth or survival benefits from this exchange.

Mitochondrial fragmentation

A change in morphology of mitochondria from a highly branched network to a fragmented vesicular form.

Acid proteolysis

Enzyme-catalysed protein breakdown promoted by an acidic environment.

Preinvasive cancer cells

Neoplastic epithelial cells that in vivo have not breached the basement membrane, usually referred to as carcinoma in situ.

T cell anergy

A tolerance mechanism in which a functionally inactive lymphocyte remains alive in a hyporesponsive state.

Antacids

Substances that neutralize acidity, especially in the stomach.

Zollinger–Ellison syndrome

A disease in which tumours in the pancreas or the upper part of the small intestine provoke an overproduction of acid into the stomach, resulting in peptic ulcers.

Transarterial embolization

A surgical procedure aiming to block blood supply to a tumour or an abnormal area of tissue.

Hypokalaemia

A deficiency of potassium in the blood serum.

QT interval prolongation

An abnormally prolonged interval between the start of the Q wave and the end of the T wave in the electrical cycle of the heart, which may lead to cardiac arrest.

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Corbet, C., Feron, O. Tumour acidosis: from the passenger to the driver's seat. Nat Rev Cancer 17, 577–593 (2017). https://doi.org/10.1038/nrc.2017.77

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