Extracellular ATP in cancer

Adenosine triphosphate (ATP) is the primary energy source and storage molecule within eukaryotic cells, acting as a donor in most endergonic reactions. For this reason, its intracellular concentration typically ranges between 5 and 10 millimolar. In contrast, the extracellular ATP (eATP) concentration is very low (nanomolar) due to the absence of enzymes responsible for its production outside the cells and the presence of ubiquitous ectonucleotidases, which degrade ATP into adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine [1]. For this reason, any condition that causes cellular damage leads to an immediate increase in eATP, which triggers a series of signaling pathways known as purinergic signaling through the activation of its receptors on surrounding cells. Some microenvironments characterized by continuous cell necrosis or active nucleotide release exhibit exceptionally high amounts of eATP. Among these, the tumor microenvironment (TME) stands out, as the uncontrolled proliferation of cancer cells and the scarcity of blood vessels often lead to necrosis [2]. The high content of eATP in tumors has been well-known since the beginning of this century [3], thanks to an extensive literature body made possible by the development of probes allowing for eATP measurement in live animals. As such, eATP is considered an established characteristic of the TME [4,5], which was even exploited to develop antitumoral agents to be released solely at cancer sites [6,7]. Moreover, the amounts of eATP increase following classical antitumor interventions such as chemotherapy or radiotherapy [8–11] and can, in turn, due to the activity of ectonucleotidases CD39 (ectonucleoside triphosphate diphosphohydrolase 1) and CD73 (ecto-5’- nucleotidase), cause a rise in the extracellular concentration of adenosine, the primary derivative of ATP hydrolysis, and a known immunosuppressive and vascularization promoting agent in the TME [12].