Extracellular adenosine triphosphate and adenosine in cancer.
Adenosine triphosphate (ATP) is actively released in the extracellular environment in response to tissue damage and cellular stress. Through the activation of P2X and P2Y receptors, extracellular ATP enhances tissue repair, promotes the recruitment of immune phagocytes and dendritic cells, and acts as a co-activator of NLR family, pyrin domain-containing 3 (NLRP3) inflammasomes. The conversion of extracellular ATP to adenosine, in contrast, essentially through the enzymatic activity of the ecto-nucleotidases CD39 and CD73, acts as a negative-feedback mechanism to prevent excessive immune responses. Here we review the effects of extracellular ATP and adenosine on tumorigenesis. First, we summarize the functions of extracellular ATP and adenosine in the context of tumor immunity. Second, we present an overview of the immunosuppressive and pro-angiogenic effects of extracellular adenosine. Third, we present experimental evidence that extracellular ATP and adenosine receptors are expressed by tumor cells and enhance tumor growth. Finally, we discuss recent studies, including our own work, which suggest that therapeutic approaches that promote ATP-mediated activation of inflammasomes, or inhibit the accumulation of tumor-derived extracellular adenosine, may constitute effective new means to induce anticancer activity.
Stagg
J
J
Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. john.stagg@petermac.org
Smyth
M J
MJ
D000241:Adenosine / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology*; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D007109:Immunity; D007165:Immunosuppression Therapy; D009369:Neoplasms / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015398:Signal Transduction
D018047:Receptors, Purinergic P1; D000255:Adenosine Triphosphate; D000241:Adenosine