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Review ArticleReview Article

ATP and Adenosine Metabolism in Cancer: Exploitation for Therapeutic Gain

Gennady G. Yegutkin and Detlev Boison
Stephen Alexander, ASSOCIATE EDITOR
Pharmacological Reviews July 2022, 74 (3) 799-824; DOI: https://doi.org/10.1124/pharmrev.121.000528
Gennady G. Yegutkin
MediCity Research Laboratory and InFLAMES Flagship, University of Turku, Turku, Finland (G.G.Y.); Department of Neurosurgery, Robert Wood Johnson and New Jersey Medical Schools, Rutgers University, Piscataway, New Jersey (D.B.); and Rutgers Brain Health Institute, Piscataway, New Jersey (D.B.)
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Detlev Boison
MediCity Research Laboratory and InFLAMES Flagship, University of Turku, Turku, Finland (G.G.Y.); Department of Neurosurgery, Robert Wood Johnson and New Jersey Medical Schools, Rutgers University, Piscataway, New Jersey (D.B.); and Rutgers Brain Health Institute, Piscataway, New Jersey (D.B.)
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Stephen Alexander
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Abstract

Adenosine is an evolutionary ancient metabolic regulator linking energy state to physiologic processes, including immunomodulation and cell proliferation. Tumors create an adenosine-rich immunosuppressive microenvironment through the increased release of ATP from dying and stressed cells and its ectoenzymatic conversion into adenosine. Therefore, the adenosine pathway becomes an important therapeutic target to improve the effectiveness of immune therapies. Prior research has focused largely on the two major ectonucleotidases, ectonucleoside triphosphate diphosphohydrolase 1/cluster of differentiation (CD)39 and ecto-5′-nucleotidase/CD73, which catalyze the breakdown of extracellular ATP into adenosine, and on the subsequent activation of different subtypes of adenosine receptors with mixed findings of antitumor and protumor effects. New findings, needed for more effective therapeutic approaches, require consideration of redundant pathways controlling intratumoral adenosine levels, including the alternative NAD-inactivating pathway through the CD38-ectonucleotide pyrophosphatase phosphodiesterase (ENPP)1-CD73 axis, the counteracting ATP-regenerating ectoenzymatic pathway, and cellular adenosine uptake and its phosphorylation by adenosine kinase. This review provides a holistic view of extracellular and intracellular adenosine metabolism as an integrated complex network and summarizes recent data on the underlying mechanisms through which adenosine and its precursors ATP and ADP control cancer immunosurveillance, tumor angiogenesis, lymphangiogenesis, cancer-associated thrombosis, blood flow, and tumor perfusion. Special attention is given to differences and commonalities in the purinome of different cancers, heterogeneity of the tumor microenvironment, subcellular compartmentalization of the adenosine system, and novel roles of purine-converting enzymes as targets for cancer therapy.

Significance Statement The discovery of the role of adenosine as immune checkpoint regulator in cancer has led to the development of novel therapeutic strategies targeting extracellular adenosine metabolism and signaling in multiple clinical trials and preclinical models. Here we identify major gaps in knowledge that need to be filled to improve the therapeutic gain from agents targeting key components of the adenosine metabolic network and, on this basis, provide a holistic view of the cancer purinome as a complex and integrated network.

Footnotes

  • This work was supported by National Institutes of Health National Institute of Neurologic Disorders and Stroke [Grant NS103740] and [Grant NS065957] and CURE Epilepsy [Catalyst Award].

  • Detlev Boison is cofounder and Chief Development Officer of PrevEp Inc.

  • https://doi.org/10.1124/pharmrev.121.000528.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 74 (3)
Pharmacological Reviews
Vol. 74, Issue 3
1 Jul 2022
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Review ArticleReview Article

Adenosine in Cancer

Gennady G. Yegutkin and Detlev Boison
Pharmacological Reviews July 1, 2022, 74 (3) 799-824; DOI: https://doi.org/10.1124/pharmrev.121.000528

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Review ArticleReview Article

Adenosine in Cancer

Gennady G. Yegutkin and Detlev Boison
Pharmacological Reviews July 1, 2022, 74 (3) 799-824; DOI: https://doi.org/10.1124/pharmrev.121.000528
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  • Article
    • Abstract
    • I. Introduction
    • II. Overview of Cellular Purine Turnover
    • III. Major Enzymes and Enzyme Families Involved in Cellular Adenosine Metabolism
    • IV. Hallmarks of Cancer Cell Metabolism
    • V. Dysregulation of Adenosine Metabolism in Cancer
    • VI. Adenosine Metabolism in Cancer: Exploitation for Therapeutic Gain
    • VII. Current Advances and Challenges in Targeting ATP and Adenosine Metabolism in Cancer
    • VIII. Conclusions and Outlook
    • Acknowledgments
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