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Review
. 2017 Jan 19;36(3):293-303.
doi: 10.1038/onc.2016.206. Epub 2016 Jun 20.

Extracellular Purines, Purinergic Receptors and Tumor Growth

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Free PMC article
Review

Extracellular Purines, Purinergic Receptors and Tumor Growth

F Di Virgilio et al. Oncogene. .
Free PMC article

Abstract

Virtually, all tumor cells as well as all immune cells express plasma membrane receptors for extracellular nucleosides (adenosine) and nucleotides (ATP, ADP, UTP, UDP and sugar UDP). The tumor microenvironment is characterized by an unusually high concentration of ATP and adenosine. Adenosine is a major determinant of the immunosuppressive tumor milieu. Sequential hydrolysis of extracellular ATP catalyzed by CD39 and CD73 is the main pathway for the generation of adenosine in the tumor interstitium. Extracellular ATP and adenosine mold both host and tumor responses. Depending on the specific receptor activated, extracellular purines mediate immunosuppression or immunostimulation on the host side, and growth stimulation or cytotoxicity on the tumor side. Recent progress in this field is providing the key to decode this complex scenario and to lay the basis to harness the potential benefits for therapy. Preclinical data show that targeting the adenosine-generating pathway (that is, CD73) or adenosinergic receptors (that is, A2A) relieves immunosuppresion and potently inhibits tumor growth. On the other hand, growth of experimental tumors is strongly inhibited by targeting the P2X7 ATP-selective receptor of cancer and immune cells. This review summarizes the recent data on the role played by extracellular purines (purinergic signaling) in host-tumor interaction and highlights novel therapeutic options stemming from recent advances in this field.

Figures

Figure 1
Figure 1
Increased extracellular ATP concentration at tumor sites. Healthy (a) or human ovarian carcinoma (OVCAR)-bearing (b and c) nude/nude mice were intraperitoneally (i.p.) injected with 2 × 106 HEK293-pmeLUC cells and monitored for luminescence emission. Luminescence was measured starting at day 2 after pmeLUC cell inoculation, and every 2 days thereafter for a total of 16 days. No luminescence was detected from healthy mice (a), except for a minor emission likely due to tissue damage following i.p. injection. On the contrary, strong light emission was detected from tumor-bearing mice (b). Luminescence was localized at discrete sites that, at post-mortem analysis, coincided with metastases on the visceral abdominal wall (c). Excised metastases were also strongly luminescent (d). Modified from Pellegatti et al.
Figure 2
Figure 2
ATP release pathways, receptors and degrading enzymes involved in purinergic signaling. ATP is released into the extracellular space via secretory vesicles (exocytosis), plasma membrane-derived microvesicles, transporters (for example, ABC cassettes), channels (for example, pannexin-1 or connexins) or through the P2X7R itself. Once in the extracellular milieu, ATP acts at P2X and P2Y receptors, and is also hydrolyzed to ADP and AMP by ENTPDases such as CD39. ADP activates P2YR12 and is further degraded to adenosine (ADO) by CD73. CD73-generated adenosine activates adenosine receptors (P1) and is degraded to inosine by adenosine deaminase.
Figure 3
Figure 3
Purinergic signaling modulates multiple steps in tumor progression. Extracellular nucleotides and nucleosides participate in all the main phases of tumor progression with opposite effects (red, supporting tumor growth; green, opposing tumor growth), depending on the specific receptor subtype activated. Hypoxia in the tumor core causes accumulation of ATP and adenosine, and promotes CD73, CD39, A2AR and A2BR expression. In addition, hypoxia also promotes expression of P2X7R and CD73, which in turn stimulate angiogenesis. Nucleotides and their receptors promote extracellular matrix degradation and tissue invasion (P2X7R and P2Y2R), tumor cell migration, extravasation and metastatic dissemination (P2Y2R, P2X7R and P2Y12R).
Figure 4
Figure 4
Role of purinergic receptors in immuno-editing. Purinergic signaling has a crucial role in tumor–host interaction. Cancer cell elimination is facilitated by activation of the P2X7R receptor expressed by dendritic cells, which helps presentation of tumor antigens to T lymphocytes. On the other hand, CD39 and CD73 promote accumulation of adenosine into the tumor microenvironment and activation of immunosuppressive A2AR. The P2X7R may also participate in tumor escape, albeit with an as yet poorly understood role, as it drives release of immunosuppressive factors from MDSCs and supports M2 macrophage and regulatory T-cell responses.

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