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Immunity, inflammation and cancer: a leading role for adenosine

Key Points

  • Several lines of evidence highlight the importance of adenosine as a crucial regulatory autocrine and paracrine factor that accumulates in the neoplastic microenvironment.

  • The concentrations of adenosine, which is physiologically present at low levels in the interstitial fluids of unstressed tissues, can rapidly increase in response to pathological conditions, such as hypoxia, ischaemia, inflammation or trauma. After being released from the intracellular space into the extracellular space, adenosine functions as an 'alarm' or danger signal and, through the activation of specific receptors, it generates various cellular responses that aim to restore tissue homeostasis.

  • The persistence of increased adenosine levels beyond the acute injury phase can become detrimental to tissues because it can activate pathways that promote and maintain an unremitting wound-healing process. These pathways lead to fibrotic remodelling or trigger several immune and tissue reactions that promote neoplastic changes.

  • Extracellular adenosine, which is usually present at high concentrations in cancer tissues, is a crucial mediator in the alteration of immune cell functions in cancer. This is possibly because the tightly regulated adenosine receptor pathways of immune cells undergo substantial alterations in tumours, thereby switching the functions of these cells from immune surveillance and host defence to the promotion of cancer cell transformation and growth.

  • Beyond the task of providing an immune-tolerant tumour microenvironment by helping to determine the activity of immune and inflammatory cells, the adenosine system directly regulates cancer growth and metastatic dissemination through specific receptors that are expressed on cancer cells.

  • Although the strategy of counteracting the growth and progression of malignancies through the pharmacological modulation of adenosine receptors and/or metabolism has been shown to work in vitro and in animal models, the translation of these results into clinical practice will require a better understanding of how adenosine helps to determine the tumour milieu and the onset and progression of tumour growth in humans.

Abstract

Cancer is a complex disease that is dictated by both cancer cell-intrinsic and cell-extrinsic processes. Adenosine is an ancient extracellular signalling molecule that can regulate almost all aspects of tissue function. As such, several studies have recently highlighted a crucial role for adenosine signalling in regulating the various aspects of cell-intrinsic and cell-extrinsic processes of cancer development. This Review critically discusses the role of adenosine and its receptors in regulating the complex interplay among immune, inflammatory, endothelial and cancer cells during the course of neoplastic disease.

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Figure 1: Adenosine and adenosine receptors.
Figure 2: The adenosine pathway in the tumour microenvironment and tumour progression.
Figure 3: The role of the adenosine system in modulating the extrinsic and intrinsic apoptotic programme.
Figure 4: CD73-derived adenosine enhances tumour cell migration via A2B adenosine receptors.

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) grant R01GM66189 (to G.H.), Hungarian Scientific Research Fund grants (Országos Tudományos Kutatási Alapprogramok (OTKA)) CK 78275 (to G.H.) and K 109178 (to G.H.), the Intramural Research Program of the NIH, the National Institute on Alcohol Abuse and Alcoholism (to P.P.), the Nexus award “Marcello Tonini” (to L.A.) and by the Inflammatory Bowel Disease (IBD) Research Foundation (mini grant 2012) (to L.A.).

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Glossary

T helper 1 cell

(TH1 cell). A CD4+ T helper cell that produces interferon-γ, interleukin-2 and tumour necrosis factor. It also promotes cell-mediated immunity and phagocyte-dependent inflammation.

CD39

(also known as ecto-nucleoside triphosphate diphosphohydrolase 1, E-NTPDase1). A membrane-bound enzyme that catalyses the conversion of extracellular ATP and/or ADP to AMP.

CD73

(also known as ecto-5′-nucleotidase, Ecto5′NTase). A membrane-bound enzyme that catalyses the conversion of extracellular AMP to adenosine.

Regulatory T cells

(TReg cells). A subpopulation of immune T cells that have a crucial role in the maintenance of immunological unresponsiveness to self antigens and in the suppression of abnormal immune responses that are deleterious to the host.

Adenosine deaminase

An enzyme that is required for the conversion of adenosine to inosine.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of cells that increase in number during cancer, inflammation and infection, and are able to potently suppress T cell responses.

Natural killer cell

(NK cell). An effector lymphocyte of the innate immune system that controls several types of tumours and microbial infections by limiting their spread.

TH17 cells

These cells, which belong to a recently identified T helper cell subset, mediate host defence mechanisms in response to various infections. These cells are also involved in the pathogenesis of several autoimmune diseases and cancer.

Prenylation

A class of lipid modification that involves covalent addition of either farnesyl or geranylgeranyl isoprenoids to conserved cysteine residues that occur at, or near, the carboxyl terminus of proteins.

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Antonioli, L., Blandizzi, C., Pacher, P. et al. Immunity, inflammation and cancer: a leading role for adenosine. Nat Rev Cancer 13, 842–857 (2013). https://doi.org/10.1038/nrc3613

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