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The role of ROS in tumour development and progression

Nature Reviews Cancer volume 22, pages 280–297 (2022)Cite this article

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Abstract

Eukaryotic cells have developed complex systems to regulate the production and response to reactive oxygen species (ROS). Different ROS control diverse aspects of cell behaviour from signalling to death, and deregulation of ROS production and ROS limitation pathways are common features of cancer cells. ROS also function to modulate the tumour environment, affecting the various stromal cells that provide metabolic support, a blood supply and immune responses to the tumour. Although it is clear that ROS play important roles during tumorigenesis, it has been difficult to reliably predict the effect of ROS modulating therapies. We now understand that the responses to ROS are highly complex and dependent on multiple factors, including the types, levels, localization and persistence of ROS, as well as the origin, environment and stage of the tumours themselves. This increasing understanding of the complexity of ROS in malignancies will be key to unlocking the potential of ROS-targeting therapies for cancer treatment.

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Fig. 1: Generation and metabolism of ROS.
Fig. 2: NADPH and glutathione metabolism.
Fig. 3: ROS and tumour progression: tumour cell survival and invasiveness.
Fig. 4: ROS and tumour progression: interactions with stromal compartments.

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Acknowledgements

This work was funded by Cancer Research UK grant C596/A26855 and supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001557 and FC001029), the UK Medical Research Council (FC001557 and FC001029) and the Wellcome Trust (FC001557 and FC001029). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. The authors thank C. Labuschagne for his advice.

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  1. The Francis Crick Institute, London, UK

    Eric C. Cheung & Karen H. Vousden

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  1. Eric C. Cheung
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The authors contributed equally to all aspects of the article.

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Correspondence to Karen H. Vousden.

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Competing interests

K.H.V. is on the Board of Directors and a shareholder of Bristol Myers Squibb, a shareholder of Illumina, Inc., on the Science Advisory Board (with stock or stock options) of PMV Pharma, RAZE Therapeutics, Kovina Therapeutics and Volastra Therapeutics, and a co-founder and consultant of Faeth Therapeutics. She has been in receipt of research funding from Astex Pharmaceuticals and AstraZeneca, and contributed to CRUK Cancer Research Technology filing of patent application WO/2017/144877. E.C.C. declares no competing interests.

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Glossary

Reactive oxygen species

(ROS). Unstable and reactive molecules that originate from oxygen during cellular metabolism.

NADPH

A reduced form of NADP+, the reducing agent for many anabolic reactions and regenerating antioxidants. Also used for generating reactive oxygen species (ROS) via NADPH oxidase (NOX).

Fenton reaction

The formation of hydroxyl radicals (·OH) and hydroperoxyl radicals from hydrogen peroxide (H2O2) and Fe2+ ions.

Mitophagy

The selective removal of dysfunctional mitochondria. Mitophagy is a type of autophagy, which is a cell intrinsic mechanism that removes and recycles unnecessary or dysfunctional cellular components and promotes short-term survival during starvation or repair during stress.

Peroxisomes

Small membrane-bound organelles that contain several reactive oxygen species (ROS)-producing and ROS-degrading enzymes for various oxidation and lipid biosynthesis reactions.

Oxidative pentose phosphate pathway

(oxPPP). An arm of the metabolic pathway that branches from glycolysis, generating NADPH and nucleotides.

Genomic instability

A high frequency of DNA mutations, chromosomal rearrangements or aneuploidy frequently seen during tumorigenesis.

Ferroptosis

A type of cell death that is dependent on iron and reactive oxygen species (ROS), promoting a toxic accumulation of oxidized lipids.

Lipid peroxidation

A chain reaction leading to the oxidation of lipids by oxidants that reacts with carbon–carbon double bonds, resulting in damaged membranes and cell death.

Cystine

An amino acid produced by the oxidation of two cysteine molecules, which are connected through a disulfide bond, and the predominant form of cysteine in cell culture media and the extracellular space.

Invadopodia

Protrusions from the cell membrane that induce degradation of the extracellular matrix and contribute to the ability of cancers to invade and metastasize.

Epithelial-to-mesenchymal transition

(EMT). A cellular process that involves losing epithelial characteristics such as intercellular contacts and cell polarity and gaining mesenchymal characteristics such as migratory and invasive properties. Essential in normal development, wound healing and fibrosis. EMT also contributes to tumour metastasis.

N-acetyl-l-cysteine

(NAC). An exogenous antioxidant, providing cysteine for glutathione synthesis and reducing free radicals via the generation of persulfides.

Cancer stem cells

(CSCs). Cancer cells that acquire some stem-like cell properties to enable them to self-renew to increase the capacity for metastasis, relapse and drug resistance.

Reductive carboxylation

A metabolic pathway that uses glutamine to produce citrate from α-ketoglutarate (α-KG) via the enzymes isocitrate dehydrogenase 1 (IDH1) and IDH2, rather than the normal tricarboxylic acid (TCA) cycle in which citrate is generated from acetyl-coenzyme A (acetyl-CoA) and oxaloacetate.

Circulating tumour cells

(CTCs). Cancer cells released into the lymphatic system or vasculature and carried around the body in blood circulation. These cells act as a precursor or seed for distant metastasis.

Electron transport chain

(Also known as the respiratory chain). Mitochondrial protein complexes that transfer electrons to create a proton gradient across the membrane, which is coupled to generate ATP via oxidative phosphorylation through ATP synthase.

Mitohormesis

Mild mitochondrial stress that increases antioxidative defences against later, higher reactive oxygen species (ROS) insults.

Angiogenesis

The growth of new blood vessels; in cancer, this refers to the development of abnormal vascularization during tumorigenesis.

Endothelial cells

Cells in a single layer that line the blood vessel.

Extravasation

The movement of cells from the blood vessels to the surrounding tissues.

Cancer-associated fibroblasts

(CAFs). Cells derived from resident normal fibroblasts or from other sites such as the endothelium or bone marrow (mesenchymal stem cells). These cells can remodel extracellular matrix or secrete factors that affect the cancer and other cells in the tumour microenvironment.

Monocytes

A type of white blood cell that gives rise to macrophages and dendritic cells.

Myeloid-derived suppressor cells

(MDSCs). Immature myeloid cells that are immunosuppressive during chronic infection and in the tumour microenvironment.

CD8+ T cell

A cytotoxic T cell that is a key component of the adaptive immune response, recognizing peptides through the T cell receptor (TCR), and able to clear infected, damaged cells and cancer cells.

Neutrophil extracellular traps

(NETs). Extracellular fibres consisting of DNA–histone complexes and proteins such as proteases and myeloperoxidase produced by neutrophils that bind pathogens extracellularly.

Tumour-associated macrophages

(TAMs). Monocyte-derived or tissue-resident macrophages (important components of the innate immune response) present in the tumour microenvironment that modulate immune suppression and angiogenesis.

CD4+ T cells

T helper cells that support the activity of other immune cells by releasing cytokines and through cell–cell interactions.

Chimeric antigen receptor (CAR) T cells

Genetically engineered T cells that produce designed T cell receptors (TCRs) against tumour cells for immunotherapy.

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Cheung, E.C., Vousden, K.H. The role of ROS in tumour development and progression. Nat Rev Cancer 22, 280–297 (2022). https://doi.org/10.1038/s41568-021-00435-0

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