The P2X7 Receptor in Oncogenesis and Metastatic Dissemination: New Insights on Vesicular Release and Adenosinergic Crosstalk

Abstract

The tumor niche is an environment rich in extracellular ATP (eATP) where purinergic receptors have essential roles in different cell subtypes, including cancer, immune, and stromal cells. Here, we give an overview of recent discoveries regarding the role of probably the best-characterized purinergic receptor in the tumor microenvironment: P2X7. We cover the activities of the P2X7 receptor and its human splice variants in solid and liquid cancer proliferation, dissemination, and crosstalk with immune and endothelial cells. Particular attention is paid to the P2X7-dependent release of microvesicles and exosomes, their content, including ATP and miRNAs, and, in general, P2X7-activated mechanisms favoring metastatic spread and niche conditioning. Moreover, the emerging role of P2X7 in influencing the adenosinergic axis, formed by the ectonucleotidases CD39 and CD73 and the adenosine receptor A2A in cancer, is analyzed. Finally, we cover how antitumor therapy responses can be influenced by or can change P2X7 expression and function. This converging evidence suggests that P2X7 is an attractive therapeutic target for oncological conditions.

Changes Induced by P2X7 Receptor Stimulation of Human Glioblastoma Stem Cells in the Proteome of Extracellular Vesicles Isolated from Their Secretome

“…They can likely increase the tumorigenic potential of GSC-derived nanoparticles, in which we previously found chaperones and metabolic enzymes as well as proteins mostly involved in cell-matrix adhesion, cell migration/aggressiveness, and chemotherapy resistance in control condition [9]. Of note, the P2X7R stimulation may occur in GBM in vivo, as the extracellular levels of ATP, the only natural agonist for these receptors, are usually higher in the TME of many tumors, including gliomas, than in the normal corresponding tissues [60].…”

“…It is increasingly evident that the purinergic ionotropic P2X7Rs are intimately implicated in the growth and metastases of many tumors [60]. P2X7Rs appear to be also involved in the release of EVs from immune and cancer cells, even though this aspect is still incompletely investigated (reviewed in [61]).…”

Purinergic enzymes on extracellular vesicles: immune modulation on the go

“…A potential immune modulatory effect of EVs containing these ‘non-canonical’ ectonucleotidases has only rarely been investigated. Notably, stimulation of the P2X7 receptor with ATP induces the release of EVs from dendritic cells (DCs), microglia and tumor cells ( 52 , 64 – 66 ). ATP-induced EVs from DCs contain IL-1β as well as the P2X7 receptor itself.…”

Mesenchymal Stem Cells and Purinergic Signaling in Autism Spectrum Disorder: Bridging the Gap between Cell-Based Strategies and Neuro-Immune Modulation

“…One of the limitations of further research is the difficulty of EV isolation (especially exosomes), which is underlain by their small nanometric sizes and heterogeneity of EVs. Only recently has some research data linked the extracellular vesicles with certain aspects of purinergic signaling by having ATP and/or Ado in their lumen, as well as active ectonucleotidases and receptors on the membrane surface [ 117 , 118 ]. The ectonucleotidase activity of CD73 is often present in EVs and even mentioned as an EVs’ surface marker.…”