Purinergic Signaling in the Hallmarks of Cancer

Abstract

Cancer is a complex expression of an altered state of cellular differentiation associated with severe clinical repercussions. The effort to characterize this pathological entity to understand its underlying mechanisms and visualize potential therapeutic strategies has been constant. In this context, some cellular (enhanced duplication, immunological evasion), metabolic (aerobic glycolysis, failure in DNA repair mechanisms) and physiological (circadian disruption) parameters have been considered as cancer hallmarks. The list of these hallmarks has been growing in recent years, since it has been demonstrated that various physiological systems misfunction in well-characterized ways upon the onset and establishment of the carcinogenic process. This is the case with the purinergic system, a signaling pathway formed by nucleotides/nucleosides (mainly adenosine triphosphate (ATP), adenosine (ADO) and uridine triphosphate (UTP)) with their corresponding membrane receptors and defined transduction mechanisms. The dynamic equilibrium between ATP and ADO, which is accomplished by the presence and regulation of a set of ectonucleotidases, defines the pro-carcinogenic or anti-cancerous final outline in tumors and cancer cell lines. So far, the purinergic system has been recognized as a potential therapeutic target in cancerous and tumoral ailments.

Keywords: ATP; adenosine; cancer; ectonucleotidase; immune evasion in cancer; purinergic receptors; purinergic signaling; tumor microenvironment.

Figure 1

Nucleotides act as autocrine and paracrine messengers. ATP is produced by oxidative phosphorylation (OXPHOS) and glycolysis intracellularly reaching mM concentrations. It can be released to extracellular space by cellular lysis, exocytosis, transporters, hemichannels of pannexin-1 (PNX-1) and P2X7R. Once located at the extracellular space, ATP activates P2XR (ligand activated ion channels), P2YR receptors (belonging to GPCR superfamily), and it can be hydrolyzed by ectonucleotidases (here, CD39 and CD73 are illustrated by their relevance in cancer) to form ADP, AMP and adenosine (ADO). ADP is able to activate P2Y12R and ADO activate G-protein coupled receptor (GPCR) receptors of the P1 family named (A1R, A2AR, A2BR and A3R). ADO is hydrolyzed by adenosine deaminase (ADA) to inosine or it is transported into the cell by nucleoside transporters (NT).

Figure 2

Purinergic signaling and tumor microenvironment (TME). (A) Cancer cells synthetize ATP rather from aerobic glycolysis (Warburg effect) which leads to lactate formation and subsequent extracellular acidification. (B) ATP is released from tumor cells (pannexin-1 hemichannels and P2X7R have an outstanding role) by general mechanisms or by cellular lysis as result of anticancer therapies and reach hundreds of mM levels, sufficient to activate any P2 receptor. (C) extracellular ATP in autocrine/paracrine way activate P2 receptors (mainly P2X7R and P2Y2R) to induce proliferation, migration and epithelial to mesenchymal transition (EMT) of cancer cells. (D) In TME, ATP is hydrolyzed to ADO by subsequent action of ectonucleotidases CD39 and CD73, which are expressed in the own tumor cells, exosomes and immune cells (i.e., CD4+, CD25+, Foxp3+ Treg); contributing to the significant increase of ADO, which in turn inhibits antitumor response of innate immune cells and T effector cells (CD4+ and CD8+). (E) ADO also contributes to monocyte differentiation into associated tumor macrophages 2s), which also amplify ADO formation.