ATP in the tumour microenvironment drives expression of nfP2X7, a key mediator of cancer cell survival

Gilbert, S.M.; Oliphant, CJ; Hassan, Sandra; Peille, AL; Bronsert, Peter; Falzoni, Simonetta; Virgilio, Francesco Di; McNulty, Shaun; Lara, Romain

doi:10.1038/s41388-018-0426-6

Cited by 153 publications

(207 citation statements)

References 47 publications

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“…Another form of P2X7R, which is not able to form a functional pore and termed as non-pore functional P2X7R (nfP2X7R), has been described recently [101]. Researchers found that antibodies against amino acid sequence specifically for nfP2X7R also had a key role in cancer growth [108], which documented that antagonists specifically for nfP2X7R may be potential effective therapeutic agents in cancer therapy.…”

Section: P2 Receptors As Tumor Therapeutic Targetsmentioning

confidence: 99%

The yin and yang functions of extracellular ATP and adenosine in tumor immunity

Cai

Zhu

et al. 2020

Cancer Cell Int

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Extracellular adenosine triphosphate (eATP) and its main metabolite adenosine (ADO) constitute an intrinsic part of immunological network in tumor immunity. The concentrations of eATP and ADO in tumor microenvironment (TME) are controlled by ectonucleotidases, such as CD39 and CD73, the major ecto-enzymes expressed on immune cells, endothelial cells and cancer cells. Once accumulated in TME, eATP boosts antitumor immune responses, while ADO attenuates immunity against tumors. eATP and ADO, like yin and yang, represent two opposite aspects from immuneactivating to immune-suppressive signals. Here we reviewed the functions of eATP and ADO in tumor immunity and attempt to block eATP hydrolysis, ADO formation and their contradictory effects in tumor models, allowing the induction of effective anti-tumor immune responses in TME. These attempts documented that therapeutic approaches targeting eATP/ADO metabolism and function may be effective methods in cancer therapy.

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Section: P2 Receptors As Tumor Therapeutic Targetsmentioning

confidence: 99%

The yin and yang functions of extracellular ATP and adenosine in tumor immunity

Cai

Zhu

et al. 2020

Cancer Cell Int

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“…The P2X7 receptor is found in several types of tumors, such as neuroblastoma, melanoma, prostate, lung, and breast cancer. P2X7 expression is commonly associated with cancer cell survival, proliferation, and metastatic potential; upon dysregulation, the P2X7 receptor is associated with tumor initiation and development ( Gilbert et al, 2019 ).…”

Section: Cancermentioning

confidence: 99%

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

2020

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Complex dynamic cellular networks have been studied in physiological and pathological processes under the light of single-cell calcium imaging (SCCI), a method that correlates functional data based on calcium shifts operated by different intracellular and extracellular mechanisms integrated with their cell phenotypes. From the classic synaptic structure to tripartite astrocytic model or the recent quadripartite microglia added ensemble, as well as other physiological tissues, it is possible to follow how cells signal spatiotemporally to cellular patterns. This methodology has been used broadly due to the universal properties of calcium as a second messenger. In general, at least two types of receptor operate through calcium permeation: a fast-acting ionotropic receptor channel and a slow-activating metabotropic receptor, added to exchangers/transporters/pumps and intracellular Ca 2+ release activated by messengers. These prototypes have gained an enormous amount of information in dynamic signaling circuits. SCCI has also been used as a method to associate phenotypic markers during development and stage transitions in progenitors, stem, vascular cells, neuro- and glioblasts, neurons, astrocytes, oligodendrocytes, and microglia that operate through ion channels, transporters, and receptors. Also, cancer cells or inducible cell lines from human organoids characterized by transition stages are currently being used to model diseases or reconfigure healthy cells in terms of the expression of calcium-binding/permeable molecules and shed light on therapy.

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“…In healthy tissues, P2X7 is expressed mainly in the central nervous system (CNS), peripheral nervous system (PNS), and in immune cells, which supports its emergence as a target for chronic pain and chronic inflammatory diseases . P2X7 is also overexpressed in a number of cancer types, potentially driving tumor development and survival (Adinolfi et al, 2002;Adinolfi et al, 2009;Adinolfi et al, 2012;Barden et al, 2014;Amoroso et al, 2015;Barden et al, 2016;Gilbert et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

et al. 2020

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P2X7 is a transmembrane receptor expressed in multiple cell types including neurons, dendritic cells, macrophages, monocytes, B and T cells where it can drive a wide range of physiological responses from pain transduction to immune response. Upon activation by its main ligand, extracellular ATP, P2X7 can form a nonselective channel for cations to enter the cell. Prolonged activation of P2X7, via high levels of extracellular ATP over an extended time period can lead to the formation of a macropore, leading to depolarization of the plasma membrane and ultimately to cell death. Thus, dependent on its activation state, P2X7 can either drive cell survival and proliferation, or induce cell death. In cancer, P2X7 has been shown to have a broad range of functions, including playing key roles in the development and spread of tumor cells. It is therefore unsurprising that P2X7 has been reported to be upregulated in several malignancies. Critically, ATP is present at high extracellular concentrations in the tumor microenvironment (TME) compared to levels observed in normal tissues. These high levels of ATP should present a survival challenge for cancer cells, potentially leading to constitutive receptor activation, prolonged macropore formation and ultimately to cell death. Therefore, to deliver the proven advantages for P2X7 in driving tumor survival and metastatic potential, the P2X7 macropore must be tightly controlled while retaining other functions. Studies have shown that commonly expressed P2X7 splice variants, distinct SNPs and posttranslational receptor modifications can impair the capacity of P2X7 to open the macropore. These receptor modifications and potentially others may ultimately protect cancer cells from the negative consequences associated with constitutive activation of P2X7. Significantly, the effects of both P2X7 agonists and antagonists in preclinical tumor models of cancer demonstrate the potential for agents modifying P2X7 function, to provide innovative cancer therapies. This review summarizes recent advances in understanding of the structure and functions of P2X7 and how these impact P2X7 roles in cancer progression. We also review potential therapeutic approaches directed against P2X7.

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ATP in the tumour microenvironment drives expression of nfP2X7, a key mediator of cancer cell survival

Cited by 153 publications

References 47 publications

The yin and yang functions of extracellular ATP and adenosine in tumor immunity

The yin and yang functions of extracellular ATP and adenosine in tumor immunity

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

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