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The role of nitric oxide in tumour progression

Key Points

  • Nitric oxide (NO) is synthesized by nitric oxide synthases (NOSs), which are ubiquitously expressed in malignant tumours. NO regulates several physiological processes through the soluble-guanylyl-cyclase–cGMP pathway and S-nitrosylation, and has cytotoxic and genotoxic effects at high concentrations.

  • Tumour-cell-derived NO promotes tumour progression by induction of tumour-cell invasion, proliferation and the expression of angiogenic factors. The inducible isoform of NOS (iNOS), which produces high concentrations of NO, mediates neoplastic transformation in oncogene- and chemical-induced tumorigenesis models, although conflicting results are reported in the literature. Conversely, the transfection of iNOS-expressing constructs into NO-sensitive tumour cells inhibits tumour growth and metastasis.

  • Host stromal-cell-derived NO, which is synthesized by iNOS, inhibits growth of NO-sensitive tumours but promotes growth of NO-resistant tumours.

  • NO that is predominantly synthesized by endothelial NOS (eNOS) in vascular endothelial cells promotes angiogenesis directly and functions both upstream and downstream of angiogenic stimuli. Moreover, NO mediates recruitment of perivascular cells and, therefore, remodelling and maturation of blood vessels. NO that is synthesized by eNOS promotes tumour progression through the maintenance of blood flow, induction of vascular hyperpermeability and reduction of leukocyte–endothelial interactions.

  • Induction of NO signalling can induce direct tumour-cell cytotoxicity or sensitize tumour cells to other treatments such as radiation. Conversely, blockade of NO signalling can inhibit neoplastic transformation, tumour angiogenesis and blood flow.

  • Expression, activity and localization of NOS isoforms, concentration and duration of NO exposure, and cellular sensitivity to NO are important determinants of NO function. Further in vivo tumour studies with high spatial and temporal resolution should resolve conflicting issues in NO biology and guide the manipulation of NO signalling for future clinical use.

Abstract

Nitric oxide (NO) and nitric oxide synthases are ubiquitous in malignant tumours and are known to exert both pro- and anti-tumour effects. We summarize our current understanding of the role of NO in tumour progression, especially in relation to angiogenesis and vascular functions. We also discuss potential strategies for cancer treatment that modulate NO production and/or its downstream signalling pathways.

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Figure 1: Production of nitric oxide (NO) in tumours.
Figure 2: Mechanisms of action of NO on tumour cells.
Figure 3: Mechanisms of action of NO on host cells.

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Acknowledgements

We thank J. Hagendoorn, K. Kozak, and J. Lahdenranta for their helpful comments. This work was supported by grants from the National Cancer Institute.

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DATABASES

National Cancer Institute

brain tumour

breast cancer

colon cancer

head and neck tumour

lung tumour

ovarian cancer

stomach tumour

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Glossary

S-nitrosylation

A post-translational modification of protein by the covalent addition of a nitrogen monoxide group to the thiol side chain of a cysteine residue of a protein or peptide. It is used in mammalian cells to convey several specific signals that are elicited by nitric oxide.

Electron abstraction

A chemical reaction or transformation that results in the bimolecular removal of an electron from a molecular entity. Molecular scavenging of electrons can produce free radicals. Free radicals are reactive species that can modify DNA, lipids and proteins.

Caspases

A family of cysteine proteases. Activated caspases initiate the apoptotic signal or execute a phase of apoptosis when cells receive an apoptosis-inducing signal. Apoptotic cell death is inhibited by S-nitrosylation in the catalytic site of caspases.

Reperfusion

The restoration of blood supply to an organ or tissue that has been starved of oxygen because of a decrease in normal blood supply. Post-ischaemia reperfusion often leads to the generation of oxygen radicals.

Pericytes

Specialized mesenchymal-like cells that are found in close association with the walls of small blood vessels. Normal pericytes share a basement membrane with vascular endothelial cells and are important for blood-vessel maturation, stabilization, remodelling and function. In tumours, the morphology and function of pericytes are often abnormal.

Extravasation

The exit of molecules or cells from blood vessels to the perivascular region.Here, this term is used for plasma leakage from vessels.

Farnesyltransferase inhibitors

A class of chemical agents that selectively inhibit farnesyltransferase. Farnesyltransferase is responsible for the transfer of a farnesyl group to Ras oncoproteins and other proteins that are involved in signalling for cell transformation and survival, which is usually abnormally active in cancer.

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Fukumura, D., Kashiwagi, S. & Jain, R. The role of nitric oxide in tumour progression. Nat Rev Cancer 6, 521–534 (2006). https://doi.org/10.1038/nrc1910

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