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How protons pave the way to aggressive cancers

Nature Reviews Cancer volume 23, pages 825–841 (2023)Cite this article

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Abstract

Cancers undergo sequential changes to proton (H+) concentration and sensing that are consequences of the disease and facilitate its further progression. The impact of protonation state on protein activity can arise from alterations to amino acids or their titration. Indeed, many cancer-initiating mutations influence pH balance, regulation or sensing in a manner that enables growth and invasion outside normal constraints as part of oncogenic transformation. These cancer-supporting effects become more prominent when tumours develop an acidic microenvironment owing to metabolic reprogramming and disordered perfusion. The ensuing intracellular and extracellular pH disturbances affect multiple aspects of tumour biology, ranging from proliferation to immune surveillance, and can even facilitate further mutagenesis. As a selection pressure, extracellular acidosis accelerates disease progression by favouring acid-resistant cancer cells, which are typically associated with aggressive phenotypes. Although acid–base disturbances in tumours often occur alongside hypoxia and lactate accumulation, there is now ample evidence for a distinct role of H+-operated responses in key events underpinning cancer. The breadth of these actions presents therapeutic opportunities to change the trajectory of disease.

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Fig. 1: Disturbances to the acid-handling cascade in tumours.
Fig. 2: The relationship between pHe and pHi can be dynamic in cancer.
Fig. 3: The acidic tumour microenvironment alters cancer cell phenotypes.
Fig. 4: The acidic tumour microenvironment shapes the interactions between cancer and stromal cells.

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Acknowledgements

Related work in the authors’ laboratories was supported by the European Research Council (SURVIVE 723997 to P.S.); the H2020 (H2020-MSCA-ITN-2018, 813834 to P.S. and S.F.P.); the Danish Cancer Society (R269-A15823 to S.F.P.; R269-A15761 to E.B.); the Independent Research Fund Denmark (0135-00139B and 0134-00218B to S.F.P.; 7025-00050B and 2034-00185B to E.B.); the Novo Nordisk Foundation (NNF21OC0069598 to S.F.P.; NNF18OC0053037 to E.B.); and the Aarhus University Research Foundation (AUFF-E-2021-9-18 to E.B.). The authors gratefully acknowledge valuable discussions with their colleagues during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

    Pawel Swietach

  2. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Ebbe Boedtkjer

  3. Department of Biology, University of Copenhagen, University of Copenhagen, Faculty of Science, København, Denmark

    Stine Falsig Pedersen

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  1. Pawel Swietach
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  2. Ebbe Boedtkjer
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  3. Stine Falsig Pedersen
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The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Pawel Swietach, Ebbe Boedtkjer or Stine Falsig Pedersen.

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Competing interests

E.B. is inventor on a patent addressing NBCn1 inhibition in cancer (EP-3271402). S.F.P. is a co-founder of SOLID Therapeutics. P.S. declares no competing interests.

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Nature Reviews Cancer thanks Olivier Feron, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Buffer therapy

An intervention aimed at raising the extracellular buffering capacity of tumours, achieved by delivering an exogenous buffer (such as Tris) or raising the level of a physiological buffer (notably CO2/HCO3–).

Carbonic anhydrases

A widely expressed family of enzymes that catalyse CO2 hydration and its reverse reaction, with catalytic sites that can be intracellular or extracellular.

Clastogenic effect

A mutagenic action that causes structural changes in DNA, resulting in the deletion, insertion or rearrangement of entire segments of a chromosome.

Fermentative metabolism

The glycolytic processing of carbohydrates that ends in the production and excretion of lactate and H+, yielding two molecules of ATP per glucose.

H+ equivalent

A species that is in chemical equilibrium with H+, such as CO2, lactic acid, HCO3–, CO32– and OH–, the membrane transport of which produces a change in pH in the adjoining aqueous compartments.

Ion trapping

A phenomenon in which weakly basic drugs become protonated in acidic compartments and less permeable across membranes, resulting in the accumulation of the drug.

Lactylation

A post-translational modification in which lactate undergoes a condensation reaction with an amino acid residue such as lysine on proteins such as histones.

Matrisome

The complete set of extracellular matrix proteins that comprises about a thousand proteins in mammals and is usually divided into the core matrisome, including collagens, glycoproteins and proteoglycans, and the matrisome-associated proteins, such as regulators and secreted factors.

Metabolon

A spatial arrangement of enzymes or transporters representing sequential steps in a more complex biological pathway that, in the case of pHi regulation, has been suggested to involve carbonic anhydrases and H+ or H+-equivalent transporters.

Net acid extrusion

A membrane transport process that results in an increase in intracellular pH, arising from the export of H+ or the import of HCO3– or similar H+ equivalents.

Oxidative phosphorylation

(OXPHOS). The mitochondrial process through which oxidation of substrates produces CO2 and an H+ gradient across the inner mitochondrial membrane, driving ATP production and yielding up to 38 molecules of ATP per glucose.

Oxygen partial pressure

(pO2). A measure of the concentration of oxygen dissolved in a solution, related to the pressure that oxygen gas exerts.

Paraptosis-like cell death

A type of programmed cell death distinct from apoptosis and necrosis, characterized by vacuolation and damage to mitochondria and endoplasmic reticulum.

pH

A dimensionless logarithmic scale that describes the acidity or basicity of a solution, where 7.0 denotes a neutral solution, below 7 denotes an acidic solution and above 7 denotes an alkaline solution.

pH buffering

A chemical reaction involving a weak acid and its conjugate base (in equilibrium with H+) that reduces — but does not eliminate — a pH change in response to the addition of acids or bases, for example, from a metabolic or membrane transport source.

pHe–pHi relationship

A graphical representation of the effect that changes in pHe have on steady-state pHi, from which sensitivity can be inferred by measuring the slope.

pK a

The negative logarithm of the acid dissociation constant (Ka = [A–] × [H+]/[HA]), which is used to categorize substances as weakly acidic (3 < pKa < 7), strongly acidic (pKa < 3), weakly basic (7 < pKa < 11) or strongly basic (pKa > 11).

Protonation

The reversible binding of H+ to a chemical moiety, such as a carboxylate, amine or imidazole, that in the case of proteins can affect structure and function.

Secondary active transport

A form of membrane transport that leads to uphill movement of a solute and is energized by a coupled downhill movement of another solute, typically sodium ions.

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Swietach, P., Boedtkjer, E. & Pedersen, S.F. How protons pave the way to aggressive cancers. Nat Rev Cancer 23, 825–841 (2023). https://doi.org/10.1038/s41568-023-00628-9

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