Expression of P2X7 Receptor Increases<i>In Vivo</i>Tumor Growth

Adinolfi, Elena; Raffaghello, Lizzia; Giuliani, Albrecht; Cavazzini, Luigi; Capece, Marina; Chiozzi, Paola; Bianchi, Giovanna; Kroemer, Guido; Pistoia, Vito; Virgilio, Francesco Di

doi:10.1158/0008-5472.can-11-1947

Cited by 320 publications

(395 citation statements)

References 48 publications

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“…These conclusions were supported by experiments with siRNA. Similar effect of P2X7R on cell survival and effects of the allosteric inhibition of P2X7R were also shown on mouse pancreatic stellate cells,25 ovarian carcinoma cells38 and in vivo on melanoma cancer model 20…”

Section: Discussionsupporting

confidence: 63%

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Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Giannuzzo

Saccomano

Napp

et al. 2016

Intl Journal of Cancer

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The ATP‐gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which includes cancer and pancreatic stellate cells (PSCs), and potentially high nucleotide/side turnover. Our aim was to determine P2X7R expression and function in human pancreatic cancer cells in vitro as well as to perform in vivo efficacy study applying P2X7R inhibitor in an orthotopic xenograft mouse model of PDAC. In the in vitro studies we show that human PDAC cells with luciferase gene (PancTu‐1 Luc cells) express high levels of P2X7R protein. Allosteric P2X7R antagonist AZ10606120 inhibited cell proliferation in basal conditions, indicating that P2X7R was tonically active. Extracellular ATP and BzATP, to which the P2X7R is more sensitive, further affected cell survival and confirmed complex functionality of P2X7R. PancTu‐1 Luc migration and invasion was reduced by AZ10606120, and it was stimulated by PSCs, but not by PSCs from P2X7‐/‐ animals. PancTu‐1 Luc cells were orthotopically transplanted into nude mice and tumour growth was followed noninvasively by bioluminescence imaging. AZ10606120‐treated mice showed reduced bioluminescence compared to saline‐treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct structures. PSCs number/activity and collagen deposition was reduced in AZ10606120‐treated tumours.

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Section: Discussionsupporting

confidence: 63%

“…This validates that the P2X7R allosteric inhibitor AZ10606120 has anti‐proliferative effects both in vitro and in vivo . This inhibitor is not yet widely tested in cancer, but two studies show that similar anti‐proliferative effect of the inhibitor was detected in subcutaneous cancer induced by HEK293‐hP2X7 or B16 melanoma cells 1, 20…”

Section: Discussionmentioning

confidence: 94%

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Giannuzzo

Saccomano

Napp

et al. 2016

Intl Journal of Cancer

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“…Tumors induced by the implant of HEK-293 cells heterologously expressing P2X7 receptors in immunodeficient mice showed elevated growth rate, an anaplastic phenotype, and high production of VEGF a well-known EMT inductor [67]. In cell lines derived from neuroblastoma or ovarian carcinoma, P2X7 receptor activity is correlated with high tumoral growth and metastatic induction, effects that involve PI3K/ AKT pathway activity [67][68][69][70]. Moreover, in pancreatic ductal adenocarcinoma cell lines, P2X7 receptor activity regulates migration and invasion, responses associated with EMT induction [71].…”

Section: Adora2amentioning

confidence: 99%

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Martinez-Ramirez

Dı́az-Muñoz

Butanda-Ochoa

et al. 2016

Purinergic Signalling

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The epithelium-mesenchymal transition (EMT) is an important process of cell plasticity, consisting in the loss of epithelial identity and the gain of mesenchymal characteristics through the coordinated activity of a highly regulated informational program. Although it was originally described in the embryonic development, an important body of information supports its role in pathology, mainly in cancerous and fibrotic processes. The purinergic system of inter-cellular communication, mainly based in ATP and adenosine acting throughout their specific receptors, has emerged as a potent regulator of the EMT in several pathological entities. In this context, cellular signaling associated to purines is opening the understanding of a new element in the complex regulatory network of this phenotypical differentiation process. In this review, we have summarized recent information about the role of ATP and adenosine in EMT, as a growing field with high therapeutic potential.Keywords P2 receptors . P1 receptors . Purinergic signaling . Cell migration . EMTThe purinergic system of intercellular communication General aspects The term purine (from: pure urine) was created more than 130 years ago by Emil Fischer after detailed analytical characterization of the uric acid molecule [1]. Purine molecular structure is the result of fusing pyrimidine and imidazole rings, and it exists as four N-H tautomeric forms [2]. Tautomerism of purine bases in DNA is one of the earliest reasons for mutations [3][4][5]. The interconversion of the different adenine or guanine tautomers produced mispairing with pyrimidines (which also show tautomeric forms) that may lead to changes in DNA sequence [6].Purine molecules appeared very early in the history of our planet, in the period known as Borganic evolution^, before the establishment of living systems. It has been postulated that purines could be formed by a eutectic (denoting a mixture of substances in fixed proportions that melts and freezes at a single temperature that is lower than the melting points of any of the separate constituents) concentration of HCN at extremely low temperature over a period of dozens of years [7]. Purine molecules, such as adenine and guanine, are components of the genetic material (DNA and RNA) of all living beings. Purine and pyrimidine tautomeric equilibria in nucleic acids was postulated to be significant in events such as DNA replication and repair as well as in the occurrence of point mutations [8].As nucleosides and nucleotides, purines play other highly strategic roles, acting as energy intermediates, allosteric regulators of key metabolic activities, redox molecules, and chemical messengers for signal transduction events. The two most important purines serving as extracellular ligands for paracrine and autocrine signaling are ATP and its dephosphorylated form, adenosine (ADO). ATP and ADO act as intracellular intermediate metabolites, and their presence in the

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“…P2 receptors are also expressed in many types of cancer [9]. Among these molecules, P2X7 receptor shows increased expression in many types of cancer cells [10][11][12][13][14]. Furthermore, activation of P2X7 receptor has been implicated in tumor growth, as well as tumor angiogenesis and metastasis of breast cancer [6, 10-12, 15, 16].…”

Section: Introductionmentioning

confidence: 99%

Autocrine signaling via release of ATP and activation of P2X7 receptor influences motile activity of human lung cancer cells

Takai

Tsukimoto

Hishida

et al. 2014

Purinergic Signalling

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Extracellular nucleotides, such as ATP, are released from cells and play roles in various physiological and pathological processes through activation of P2 receptors. Here, we show that autocrine signaling through release of ATP and activation of P2X7 receptor influences migration of human lung cancer cells. Release of ATP was induced by stimulation with TGF-β1, which is a potent inducer of cell migration, in human lung cancer H292 cells, but not in noncancerous BEAS-2B cells. Treatment of H292 cells with a specific antagonist of P2X7 receptor resulted in suppression of TGF-β1-induced migration. PC-9 human lung cancer cells released a large amount of ATP under standard cell culture conditions, and P2X7 receptor-dependent dye uptake was observed even in the absence of exogenous ligand, suggesting constitutive activation of P2X7 receptor in this cell line. PC-9 cells showed high motile activity, which was inhibited by treatment with ecto-nucleotidase and P2X7 receptor antagonists, whereas a P2X7 receptor agonist enhanced migration. PC-9 cells also harbor a constitutively active mutation in epidermal growth factor receptor (EGFR). Treatment with EGFR tyrosine kinase inhibitor AG1478 suppressed both cell migration and P2X7 receptor expression in PC-9 cells. Compared to control PC-9 cells, cells treated with P2X7 antagonist exhibited broadened lamellipodia around the cell periphery, while AG1478-treated cells lacked lamellipodia. These results indicate that P2X7-mediated signaling and EGFR signaling may regulate migration of PC-9 cells through distinct mechanisms. We propose that autocrine ATP-P2X7 signaling is involved in migration of human lung cancer cells through regulation of actin cytoskeleton rearrangement.

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Expression of P2X7 Receptor IncreasesIn VivoTumor Growth

Cited by 320 publications

References 48 publications

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Autocrine signaling via release of ATP and activation of P2X7 receptor influences motile activity of human lung cancer cells

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