Adenosine A3 Receptor and Its Potential Role in Cancer Treatment: A Narrative Review

Found in all human cells, the purine nucleoside adenosine plays various roles in different metabolic pathways. Adenosine is not stored in vesicles but is released continuously, based on metabolic demands. Essential in energy production, adenosine is a full agonist at four known receptors (A1, A2A, A2B, and A3), and is produced either intracellularly or in the extracellular space. Adenosine is the building block for adenosine triphosphate (ATP), a vasodilator that inhibits certain cerebral neurotransmissions. Adenosine diphosphate (ADP) releases energy via its phosphate bonds and can "recharge" by adding phosphate groups later on, unlike ATP. The A3 receptors are most densely expressed in humans in the liver, lungs, immune cells, heart, and brain, and A3 agonists confer cytoprotection, making A3 agonists an intriguing potential anticancer drug. A3 receptors are so highly expressed in cancer cells and tumors that they serve as cancer biomarkers. To date, A3 agonists and A2A antagonists have emerged as potential anticancer drugs. Paradoxically, A3 is upregulated in primary tumors and metastatic disease, and A3 activity correlates with invasive actions of tumor cells. This contradictory effect, paralleled by the pro- and anti-inflammatory effects of A3, may be explicable because the downregulation of A3 receptors may produce different effects than A3 agonism. Adenosine is abundant in the tumor microenvironment (TME), and cancer cells seem adept at adjusting their metabolic processes to attune themselves to their specific TME. The derangement of energy metabolism is characteristic of cancer, and cancer spreads as normal cells in proximity to a tumor become increasingly neoplastic and tumorigenic. This expands our old notion of tumors as discrete, separate bodies and views them now as complex layers of cancer cells of different functions; these cells, which can include recruited normal cells, interact with each other. The role of mast cells is emerging as an important, albeit enigmatic, part of the TME. Mast cells are abundant in tumors and appear to have a pro-inflammatory effect, but it is not entirely clear if they serve to promote or oppose the growth of tumors. Crosstalk between mast cells and some types of cancer cells, involving adenosine, has been observed. The translational impact and clinical implications of these findings remain speculative.