Abstract
Adenosine triphosphate (ATP) is one of the main biochemical components of the tumor microenvironment (TME), where it can promote tumor progression or tumor suppression depending on its concentration and on the specific ecto-nucleotidases and receptors expressed by immune and cancer cells. ATP can be released from cells via both specific and nonspecific pathways. A non-regulated release occurs from dying and damaged cells, whereas active release involves exocytotic granules, plasma membrane-derived microvesicles, specific ATP-binding cassette (ABC) transporters and membrane channels (connexin hemichannels, pannexin 1 (PANX1), calcium homeostasis modulator 1 (CALHM1), volume-regulated anion channels (VRACs) and maxi-anion channels (MACs)). Extracellular ATP acts at P2 purinergic receptors, among which P2X7R is a key mediator of the final ATP-dependent biological effects. Over the years, P2 receptor- or ecto-nucleotidase-targeting for cancer therapy has been proposed and actively investigated, while comparatively fewer studies have explored the suitability of TME ATP as a target. In this review, we briefly summarize the available evidence suggesting that TME ATP has a central role in determining tumor fate and is, therefore, a suitable target for cancer therapy.
Highlights
Our understanding of the physiological role of Adenosine triphosphate (ATP) has been greatly expanded ever since its first isolation from skeletal muscle [1]
In 1970, Geoff Burnstock demonstrated that extracellular ATP is the transmitter substance released by non-adrenergic inhibitory nerves [3], and later in 1972 formulated his “purinergic hypothesis” postulating that ATP is released by most cells as an extracellular signaling molecule [4]
Early studies focused on the role of purinergic receptors in neurotransmission, as early as 1980 it was suggested that specific plasma membrane receptors for extracellular ATP were expressed by inflammatory and cancer cells [7,8]
Summary
Our understanding of the physiological role of ATP has been greatly expanded ever since its first isolation from skeletal muscle [1]. Cells 2020, 9, 2496 stored in very high amounts within the cells (from 5 to 10 mmol/L); (c) is water-soluble and freely diffusible in the extracellular space due to negatively charged phosphate residues; (d) is rapidly degraded by ubiquitous extracellular nucleotidases; (e) ligates specific plasma membrane receptors, a feature that confers specificity to its signaling. These properties allow the generation of an extracellular messenger characterized by (a) very low background noise and high signal-to-noise ratio; (b) rapid diffusion through the aqueous tissue interstitium; (c) rapid signal shut-off to avoid overstimulation or receptor desensitization [11]. A role for eATP has been identified in several, different physiological and pathological conditions such as [12]: glial-neuron interaction [13], sensory transmission [14], hormone secretion [15], disorders of central nervous system [16], cardiovascular diseases [17], infection [18], inflammation [19] and cancer [20]
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