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Extracellular ATP and P2 purinergic signalling in the tumour microenvironment

Nature Reviews Cancer volume 18, pages 601–618 (2018)Cite this article

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Abstract

Modulation of the biochemical composition of the tumour microenvironment is a new frontier of cancer therapy. Several immunosuppressive mechanisms operate in the milieu of most tumours, a condition that makes antitumour immunity ineffective. One of the most potent immunosuppressive factors is adenosine, which is generated in the tumour microenvironment owing to degradation of extracellular ATP. Accruing evidence over the past few years shows that ATP is one of the major biochemical constituents of the tumour microenvironment, where it acts at P2 purinergic receptors expressed on both tumour and host cells. Stimulation of P2 receptors has different effects depending on the extracellular ATP concentration, the P2 receptor subtype engaged and the target cell type. Among P2 receptors, the P2X purinergic receptor 7 (P2X7R) subtype appears to be a main player in host–tumour cell interactions. Preclinical studies in several tumour models have shown that P2X7R targeting is potentially a very effective anticancer treatment, and many pharmaceutical companies have now developed potent and selective small molecule inhibitors of P2X7R. In this Review, we report on the multiple mechanisms by which extracellular ATP shapes the tumour microenvironment and how its stimulation of host and tumour cell P2 receptors contributes to determining tumour fate.

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Fig. 1: Modulation of immune cell responses by extracellular ATP in the tumour microenvironment.
Fig. 2: Stimulation of cancer cell metabolism by extracellular ATP acting at the P2X purinergic receptor P2X7R.
Fig. 3: The multiple effects of extracellular ATP on tumour cell survival, platelet activation and tumour cell intravasation and extravasation.

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Acknowledgements

F.D.V. is supported by grants from the Italian Association for Cancer Research (AIRC; IG 13025 and IG 18581) and the Ministry of Health of Italy (RF-2011-02348435). E.A. is supported by an AIRC Individual Grant (IG 16812). Both F.D.V. and E.A. are supported by institutional funds from the University of Ferrara. F.D.V. also acknowledges networking support from COST (European Cooperation in Science and Technology) Action BM-1406.

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Nature Reviews Cancer thanks S. Robson, J. Stagg and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

    Francesco Di Virgilio, Alba Clara Sarti, Simonetta Falzoni, Elena De Marchi & Elena Adinolfi

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  1. Francesco Di Virgilio
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  2. Alba Clara Sarti
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  3. Simonetta Falzoni
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F.D.V. drafted sections and revised and wrote the final version of the article. E.A., S.F., A.C.S. and E.D.M. researched data and contributed some sections. All the authors contributed to reviewing and editing before submission.

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Correspondence to Francesco Di Virgilio.

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F.D.V. is a member of the Scientific Advisory Board of Biosceptre, a UK-based biotech company involved in the development of P2X purinergic receptor 7 (P2X7R)-targeted therapeutics. E.A., S.F., A.C.S. and E.D.M. declare no competing interests.

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Glossary

Metabotropic receptors

Plasma membrane receptors coupled to the generation of an intracellular second messenger.

Ionotropic receptor

A plasma membrane receptor that, upon binding of an extracellular ligand, opens to enable transmembrane fluxes of small ions such as Na+, K+, Ca2+ and Cl−.

Ectonucleotidases

Enzymes expressed on the surface of virtually all cell types, where they catalyse the removal of one or two phosphate residues from extracellular nucleotides to eventually generate nucleosides. Ectonucleotidases participate in multiple physiological and pathophysiological responses ranging from neurotransmission to hormone secretion and from inflammation to blood coagulation.

Förster resonance energy transfer

(FRET). A physical property based on the measurement of light emission from a fluorescent molecule (acceptor) activated by an excited nearby molecule (donor) via a process of energy transfer (resonance) that does not involve emission of light.

Maxi-anion channels

Ubiquitous large-conductance, anion-selective channels that are permeable to ATP and are activated by hypoxia, ischaemia and osmotic stress.

Connexins

Proteins found in vertebrates that assemble to form gap junctions but may also function as hemi-channels in isolated cells.

Pannexin 1

A member of the pannexin family of large transmembrane channels that are permeable to ions and small solutes (for example, ATP).

Regulatory T cells

(Treg cells). A subpopulation of CD4+ T lymphocytes identified by the forkhead box protein P3 (FOXP3) transcription factor, which inhibit T cell functions via several mechanisms to down-modulate inflammation and prevent autoimmune responses. Treg cells are one of the most important immunosuppressive cell types in the tumour microenvironment.

M2 macrophages

Alternatively activated macrophages that do not express the typical markers of inflammatory macrophages (M1) and are most commonly found at sites of angiogenesis and tissue regeneration, as well as in the tumour microenvironment. M2 macrophages are weakly pro-inflammatory and mostly anti-inflammatory and immunosuppressive.

Macropinocytosis

A regulated form of endocytosis that mediates the uptake of extracellular fluid and small soluble molecules.

P2X7B

A shorter (364 amino acids long) splice variant of the human P2X purinergic receptor 7 (P2X7) subunit (the full length variant being named P2X7A) that lacks 231 carboxy-terminal residues and bears an insertion of 18 extra amino acids. P2X7B retains cation (Na+, K+ and Ca2+) channel permeability but lacks the ability to activate the large-conductance pore (macropore) associated with P2X7A activation.

Pyroptosis

A form of cell death that is triggered by inflammasome assembly and mediated by caspase 1 or caspase 11, caspase 4 and caspase 5 activation; the process culminates in gasdermin D cleavage and cell lysis. Pyroptosis is thought to be a defensive lytic mechanism to kill infected cells.

Anaplerotic reactions

Biochemical processes that generate intermediates of metabolic pathways, which are often used as building blocks for the synthesis of structural cell components.

Warburg effect

Also known as aerobic glycolysis, an effect in which cells preferentially use glycolytic as opposed to oxidative metabolism to synthesize ATP. Aerobic glycolysis was originally thought to be characteristic of tumours but is now known to be characteristic of every fast-growing tissue.

Autophagy

A self-degradative, highly conserved process by which eukaryotic cells digest damaged organelles, intracellular components and protein aggregates and eliminate intracellular pathogens.

Invadopodia

1–2 μm-long, actin-rich membrane protrusions that infiltrate and degrade the extracellular matrix and are considered a hallmark of tumour cells that are undergoing invasion and dissemination.

Thrombocytopenia

A condition characterized by a pathological decrease of platelets (thrombocytes) in the blood.

Thrombocytosis

A condition characterized by a pathological increase of platelets (thrombocytes) in the blood.

Non-functional P2X7R

(nfP2X7R). An as yet poorly characterized P2X purinergic receptor 7 (P2X7R) variant selectively expressed by some tumour types, which exposes an epitope normally hidden in the canonical P2X7R variant and lacks the ability to activate a large-conductance pore.

Nanobody

A single-domain antibody consisting of the variable domain of heavy chain antibodies naturally occurring in camelids. Nanobodies are potentially very useful because they often bind functional epitopes not accessible to conventional antibodies.

Atherothrombotic events

Events leading to the formation of a thrombus on the surface of pre-existing atherosclerotic lesions (fibrous plaques in blood vessels).

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Di Virgilio, F., Sarti, A.C., Falzoni, S. et al. Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. Nat Rev Cancer 18, 601–618 (2018). https://doi.org/10.1038/s41568-018-0037-0

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