P2X7R as an independent prognostic indicator in gastric cancer

Çalık, İlknur; Çalık, Muhammet; Sarikaya, Burcu; Ozercan, İbrahim Hanifi; Arslan, Ramazan; Artaş, Gökhan; Dağlı, Adile Ferda

doi:10.17305/bjbms.2020.4620

Cited by 22 publications

(20 citation statements)

References 34 publications

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“…While nfP2X7 was identified in the human HT-29 and Colo-205 colon cancer cell lines (Barden et al, 2009), other reports have shown P2X7 expression in human HCT8, Caco-2, Colo-205, and murine MCA38 colon cancer cell lines and the latter cell line was found to possess functional P2X7 macropore (Coutinho-Silva et al, 2005;Kunzli et al, 2011;Bian et al, 2013). Analysis of P2X7 expression in 156 gastric cancers corelated P2X7 expression with tumor burden and poor survival suggesting that P2X7 may be involved in the progression of gastric cancer (Calik et al, 2020).…”

Section: Colorectal and Gastric Cancermentioning

confidence: 88%

“…Prostate (Slater et al, 2004a;Maianski et al, 2007;Adinolfi et al, 2009;Barden et al, 2009;Ravenna et al, 2009;Adinolfi et al, 2010;Barden et al, 2014;Ghalali et al, 2014;Qiu et al, 2014;Solini et al, 2015;Barden et al, 2016;Gilbert et al, 2019) Lung (Barden et al, 2009;Takai et al, 2012;Jelassi et al, 2013;Barden et al, 2014;Takai et al, 2014;Schmid et al, 2015;Gilbert et al, 2019) Kidney (Liu et al, 2015;Gilbert et al, 2019) Colorectal (Coutinho-Silva et al, 2005;Barden et al, 2009;Li et al, 2009;Kunzli et al, 2011;Bian et al, 2013;Barden et al, 2014;Barden et al, 2016;Qian et al, 2017;Gilbert et al, 2019;) Gastric (Barden et al, 2009;Barden et al, 2014;Calik et al, 2020) Breast (Slater et al, 2004b;Barden et al, 2009;Li et al, 2009;Tafani et al, 2010;Jelassi et al, 2011;Huang et al, 2013;Jelassi et al, 2013;Barden et al, 2014;Chadet et al, 2014;<...>…”

Section: Cancer Typeunclassified

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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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Section: Colorectal and Gastric Cancermentioning

confidence: 88%

Section: Cancer Typeunclassified

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

et al. 2020

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“…In this study, we screened eight P2 receptors which were commonly reported in cancer—the vast majority of these studies relate to P2X7, P2Y2 and P2Y12 receptors ( Adinolfi et al, 2012 ; Li et al, 2013 ; Chadet et al, 2014 ; Jin et al, 2014 ). P2X7 receptors have been shown to express strongly in prostate cancer cells, in osteosarcoma, in lymphocyte-infiltrating gastric cancer, pancreatic ductal adenocarcinoma cell lines, and in patients with malignant pleural mesothelioma, and its antagonism has been shown to inhibit growth of tumors in various in vivo models ( Qiu et al, 2014 ; Giannuzzo et al, 2015 ; Amoroso et al, 2016 ; Zhang et al, 2019 ; Calik et al, 2020 ). We found this true in the case of IMR-32 neuroblastoma and MCF-7 breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Extracellular ATP Mediates Cancer Cell Migration and Invasion Through Increased Expression of Cyclooxygenase 2

2021

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The tumor microenvironment plays a major role in the ability of the tumor cells to undergo metastasis. A major player of tumors gaining metastatic property is the inflammatory protein, cyclooxygenase 2 (COX-2). Several tumors show upregulation of this protein, which has been implicated in mediating metastasis in various cancer types such as of colon, breast and lung. In this report, we show that the concentration of extracellular ATP (eATP) is increased in response to cell death mediated by chemotherapeutic agents such as doxorubicin. By using three different cell-lines—HeLa (cervical), IMR-32 (neuronal) and MCF-7 (breast)—we show that this eATP goes on to act on purinergic (P2) receptors. Among the various P2 receptors expressed in these cells we identified P2X7, in IMR-32 and MCF-7 cells, and P2Y12, in HeLa cells, as important in modulating cell migration and invasion. Downstream of the P2 receptor activation, both p42/44 mitogen-activated protein kinase (MAPK) and the p38 MAPK are activated in these cells. These result in an increase in the expression of COX-2 mRNA and protein. We also observe an increase in the activity of matrix metalloproteinase 2 (MMP-2) enzyme in these cells. Blocking the P2 receptors not only blocks migration and invasion, but also COX-2 synthesis and MMP-2 activity. Our results show the link between purinergic receptors and COX-2 expression. Increased levels of ATP in the tumor microenvironment, therefore, leads to increased COX-2 expression, which, in turn, affords migratory and invasive properties to the tumor. This provides P2 receptor-based anti-inflammatory drugs (PBAIDs) a potential opportunity to be explored as cancer therapeutics.

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“…Interestingly, an antibody directed against nfP2X7 also proved efficacious in reducing basal cell carcinoma growth in a phase I clinical trial on humans [83]. These data are of sure relevance to develop new P2X7-targeting therapies, also considering that an increasing number of studies report an association between P2X7 overexpression and bad prognosis or response to therapy in oncologic patients [42,65,72,[84][85][86][87]. The majority of these studies do not take into account known P2X7 variants, but some interesting progress was made in this field of research in last years that we cover in the present overview.…”

Section: Role Of Atp and P2x7 Receptor In Oncologymentioning

confidence: 95%

P2X7 Variants in Oncogenesis

Pegoraro

Marchi

Adinolfi

2021

Cells

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The P2X7 receptor for extracellular ATP is a well-established mediator of tumoral development and progression both in solid cancers and hematological malignancies. The human P2X7 gene is highly polymorphic, and several splice variants of the receptor have been identified in time. P2X7 single-nucleotide polymorphisms (SNPs) have been broadly analyzed by studies relating them to pathologies as different as infectious, inflammatory, nervous, and bone diseases, among which cancer is included. Moreover, in the last years, an increasing number of reports concentrated on P2X7 splice variants’ different roles and their implications in pathological conditions, including oncogenesis. Here, we give an overview of established and recent literature demonstrating a role for human P2X7 gene products in oncological conditions, mainly focusing on current data emerging on P2X7 isoform B and nfP2X7. We explored the role of these and other genetic variants of P2X7 in cancer insurgence, dissemination, and progression, as well as the effect of chemotherapy on isoforms expression. The described literature strongly suggests that P2X7 variants are potential new biomarkers and therapeutical targets in oncological conditions and that their study in carcinogenesis deserves to be further pursued.

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P2X7R as an independent prognostic indicator in gastric cancer

Cited by 22 publications

References 34 publications

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

Extracellular ATP Mediates Cancer Cell Migration and Invasion Through Increased Expression of Cyclooxygenase 2

P2X7 Variants in Oncogenesis

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