{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T01:06:49Z","timestamp":1785460009810,"version":"3.56.0"},"reference-count":112,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T00:00:00Z","timestamp":1633996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["310317\/2018-5"],"award-info":[{"award-number":["310317\/2018-5"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Gliomas are the most common malignant brain tumors in adults, characterized by a high proliferation and invasion. The tumor microenvironment is rich in growth-promoting signals and immunomodulatory pathways, which increase the tumor\u2019s aggressiveness. In response to hypoxia and glioma therapy, the amounts of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) strongly increase in the extracellular space, and the purinergic signaling is triggered by nucleotides\u2019 interaction in P2 receptors. Several cell types are present in the tumor microenvironment and can facilitate tumor growth. In fact, tumor cells can activate platelets by the ADP-P2Y12 engagement, which plays an essential role in the cancer context, protecting tumors from the immune attack and providing molecules that contribute to the growth and maintenance of a rich environment to sustain the protumor cycle. Besides platelets, the P2Y12 receptor is expressed by some tumors, such as renal carcinoma, colon carcinoma, and gliomas, being related to tumor progression. In this context, this review aims to depict the glioma microenvironment, focusing on the relationship between platelets and tumor malignancy.<\/jats:p>","DOI":"10.3390\/molecules26206146","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T06:38:41Z","timestamp":1634107121000},"page":"6146","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["P2Y12 Purinergic Receptor and Brain Tumors: Implications on Glioma Microenvironment"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2709-2801","authenticated-orcid":false,"given":"Fernanda Bueno","family":"Morrone","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia Aplicada, Escola de Ci\u00eancias da Sa\u00fade e da Vida, PUCRS, Porto Alegre 90610-001, RS, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Biologia Celular e Molecular, PUCRS, Porto Alegre 90610-001, RS, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Medicina e Ci\u00eancias da Sa\u00fade, PUCRS, Porto Alegre 90610-001, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Vargas","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia Aplicada, Escola de Ci\u00eancias da Sa\u00fade e da Vida, PUCRS, Porto Alegre 90610-001, RS, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Medicina e Ci\u00eancias da Sa\u00fade, PUCRS, Porto Alegre 90610-001, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6265-6564","authenticated-orcid":false,"given":"Liliana","family":"Rockenbach","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia Aplicada, Escola de Ci\u00eancias da Sa\u00fade e da Vida, PUCRS, Porto Alegre 90610-001, RS, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Medicina e Ci\u00eancias da Sa\u00fade, PUCRS, Porto Alegre 90610-001, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thamiris Becker","family":"Scheffel","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia Aplicada, Escola de Ci\u00eancias da Sa\u00fade e da Vida, PUCRS, Porto Alegre 90610-001, RS, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Biologia Celular e Molecular, PUCRS, Porto Alegre 90610-001, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"v1","DOI":"10.1093\/neuonc\/now207","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009\u20132013","volume":"18","author":"Ostrom","year":"2016","journal-title":"Neuro-Oncology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1124\/mol.116.103770","article-title":"Calcium Channels and Associated Receptors in Malignant Brain Tumor Therapy","volume":"90","author":"Morrone","year":"2016","journal-title":"Mol. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.critrevonc.2017.03.021","article-title":"Central nervous system gliomas","volume":"113","author":"Reni","year":"2017","journal-title":"Crit. Rev. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1179\/1743132814Y.0000000423","article-title":"Current evidence of temozolomide and bevacizumab in treatment of gliomas","volume":"37","author":"Nanegrungsunk","year":"2014","journal-title":"Neurol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1056\/NEJMoa043331","article-title":"MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma","volume":"7","author":"Hegi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1515\/med-2017-0035","article-title":"Tumor microenvironment in treatment of glioma","volume":"12","author":"Lijuan","year":"2017","journal-title":"Open Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12943-015-0469-z","article-title":"Extracellular nucleotides as novel, underappreciated pro-metastatic factors that stimulate purinergic signaling in human lung cancer cells","volume":"14","author":"Schneider","year":"2015","journal-title":"Mol. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Pellegatti, P., Raffaghello, L., Bianchi, G., Piccardi, F., Pistoia, V., and Di Virgilio, F. (2008). Increased Level of Extracellular ATP at Tumor Sites: In Vivo Imaging with Plasma Membrane Luciferase. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002599"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/s41568-018-0037-0","article-title":"Extracellular ATP and P2 purinergic signalling in the tumour microenvironment","volume":"18","author":"Sarti","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s11302-013-9372-5","article-title":"Purinergic signalling and cancer","volume":"9","author":"Burnstock","year":"2013","journal-title":"Purinergic Signal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/onc.2016.206","article-title":"Extracellular purines, purinergic receptors and tumor growth","volume":"36","author":"Adinolfi","year":"2017","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3397","DOI":"10.3389\/fonc.2020.617385","article-title":"Immunosuppression in Gliomas via PD-1\/PD-L1 Axis and Adenosine Pathway","volume":"10","author":"Scheffel","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3986","DOI":"10.1182\/blood-2004-06-2066","article-title":"Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: Coordination by extracellular nucleotide metabolism","volume":"104","author":"Eltzschig","year":"2004","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Campos-Contreras, A.D.R., D\u00edaz-Mu\u00f1oz, M., and V\u00e1zquez-Cuevas, F.G. (2020). Purinergic Signaling in the Hallmarks of Cancer. Cells, 9.","DOI":"10.3390\/cells9071612"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.tips.2007.07.002","article-title":"Liaisons dangereuses: P2X7 and the inflammasome","volume":"28","year":"2007","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4946","DOI":"10.1182\/blood-2005-07-2994","article-title":"Rapid ATP-induced release of matrix metalloproteinase 9 is mediated by the P2X7 receptor","volume":"107","author":"Gu","year":"2006","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1023\/A:1025699932270","article-title":"Extracellular Nucleotides and Nucleosides Induce Proliferation and Increase Nucleoside Transport in Human Glioma Cell Lines","volume":"64","author":"Morrone","year":"2003","journal-title":"J. Neuro-Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s11060-004-1383-1","article-title":"Increased resistance of glioma cell lines to extracellular ATP cytotoxicity","volume":"71","author":"Morrone","year":"2005","journal-title":"J. Neuro-Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"173687","DOI":"10.1016\/j.ejphar.2020.173687","article-title":"P2Y2 receptor activation promotes esophageal cancer cells proliferation via ERK1\/2 pathway","volume":"891","author":"Zaparte","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"L376","DOI":"10.1152\/ajplung.00447.2002","article-title":"ATP- and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells","volume":"285","author":"Sedehizade","year":"2003","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"28736","DOI":"10.18632\/oncotarget.7518","article-title":"Important roles of P2Y receptors in the inflammation and cancer of digestive system","volume":"7","author":"Wan","year":"2016","journal-title":"Oncotarget"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"41162","DOI":"10.18632\/oncotarget.6240","article-title":"P2X3 purinergic receptor overexpression is associated with poor recurrence-free survival in hepatocellular carcinoma patients","volume":"6","author":"Maynard","year":"2015","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s11302-021-09785-8","article-title":"Autocrine and paracrine purinergic signaling in the most lethal types of cancer","volume":"17","author":"Madariaga","year":"2021","journal-title":"Purinergic Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/j.1474-8673.2007.00389.x","article-title":"P2Y2- and P2Y4purinergic receptors are over-expressed in human colon cancer","volume":"27","author":"Nylund","year":"2007","journal-title":"Auton. Autacoid Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1111\/jth.12952","article-title":"P2Y12 receptors: Structure and function","volume":"13","author":"Cattaneo","year":"2015","journal-title":"J. Thromb. Haemost."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1038\/nn1805","article-title":"The P2Y12 receptor regulates microglial activation by extracellular nucleotides","volume":"9","author":"Haynes","year":"2006","journal-title":"Nat. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41419-019-1425-4","article-title":"P2Y12 regulates microglia activation and excitatory synaptic transmission in spinal lamina II neurons during neuropathic pain in rodents","volume":"10","author":"Yu","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sham, D., Wesley, U.V., Hristova, M., and Van Der Vliet, A. (2013). ATP-Mediated Transactivation of the Epidermal Growth Factor Receptor in Airway Epithelial Cells Involves DUOX1-Dependent Oxidation of Src and ADAM17. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054391"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"66","DOI":"10.3389\/fphar.2018.00066","article-title":"P2Y12 Receptors in Tumorigenesis and Metastasis","volume":"9","author":"Ballerini","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Elaskalani, O., Domenichini, A., Razak, N.B.A., Dye, D.E., Falasca, M., and Metharom, P. (2020). Antiplatelet Drug Ticagrelor Enhances Chemotherapeutic Efficacy by Targeting the Novel P2Y12-AKT Pathway in Pancreatic Cancer Cells. Cancers, 12.","DOI":"10.3390\/cancers12010250"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/s41582-018-0025-8","article-title":"Multidimensional communication in the microenvirons of glioblastoma","volume":"14","author":"Broekman","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/nrclinonc.2017.101","article-title":"The immune contexture in cancer prognosis and treatment","volume":"14","author":"Fridman","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S185","DOI":"10.1016\/j.semcancer.2015.03.004","article-title":"Immune evasion in cancer: Mechanistic basis and therapeutic strategies","volume":"35","author":"Vinay","year":"2015","journal-title":"Semin. Cancer Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1002\/glia.23520","article-title":"Astrocytes, the rising stars of the glioblastoma microenvironment","volume":"67","author":"Brandao","year":"2019","journal-title":"Glia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3389\/fnene.2010.00131","article-title":"Microglia in Close Vicinity of Glioma Cells: Correlation Between Phenotype and Metabolic Alterations","volume":"2","author":"Voisin","year":"2010","journal-title":"Front. Neuroenerget."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Szulzewsky, F., Pelz, A., Feng, X., Synowitz, M., Markovic, D., Langmann, T., Holtman, I.R., Wang, X., Eggen, B.J.L., and Boddeke, H.W.G.M. (2015). Glioma-Associated Microglia\/Macrophages Display an Expression Profile Different from M1 and M2 Polarization and Highly Express Gpnmb and Spp1. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116644"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"663","DOI":"10.2217\/imt.14.48","article-title":"Therapeutic targeting of tumor-associated macrophages and microglia in glioblastoma","volume":"6","author":"Bowman","year":"2014","journal-title":"Immunotherapy"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1038\/ni.3586","article-title":"Glioma and microglia, a double entendre","volume":"17","author":"Grauwet","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/s41568-019-0224-7","article-title":"Brain immunology and immunotherapy in brain tumours","volume":"20","author":"Sampson","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1093\/neuonc\/nov280","article-title":"CD4+T effector memory cell dysfunction is associated with the accumulation of granulocytic myeloid-derived suppressor cells in glioblastoma patients","volume":"18","author":"Dubinski","year":"2016","journal-title":"Neuro-Oncology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"133","DOI":"10.4103\/glioma.glioma_10_19","article-title":"Role of natural killer cells in isocitrate dehydrogenase 1\/2 mutant glioma pathogenesis and emerging therapies","volume":"2","author":"Amankulor","year":"2019","journal-title":"Glioma"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1093\/neuonc\/noq204","article-title":"Immune modulation effects of concomitant temozolomide and radiation therapy on peripheral blood mononuclear cells in patients with glioblastoma multiforme","volume":"13","author":"Fadul","year":"2011","journal-title":"Neuro-Oncology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5932","DOI":"10.1038\/onc.2008.267","article-title":"NK cells and cancer immunosurveillance","volume":"27","author":"Waldhauer","year":"2008","journal-title":"Oncogene"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Huong, P.T., Nguyen, L.T., Nguyen, X.-B., Lee, S.K., and Bach, D.-H. (2019). The Role of Platelets in the Tumor-Microenvironment and the Drug Resistance of Cancer Cells. Cancers, 11.","DOI":"10.3390\/cancers11020240"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.ccell.2018.03.002","article-title":"The Platelet Lifeline to Cancer: Challenges and Opportunities","volume":"33","author":"Haemmerle","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1002\/ijc.27441","article-title":"Tumor-platelet interaction in solid tumors","volume":"130","author":"Buergy","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1080\/09537104.2018.1453059","article-title":"The pro-inflammatory role of platelets in cancer","volume":"29","author":"Olsson","year":"2018","journal-title":"Platelets"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1158\/2159-8290.CD-12-0216","article-title":"Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow\u2013Derived Cells","volume":"2","author":"Kuznetsov","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/nrc1889","article-title":"Brain tumour stem cells","volume":"6","author":"Vescovi","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"143","DOI":"10.3389\/fonc.2017.00143","article-title":"The Impact of the Tumor Microenvironment on the Properties of Glioma Stem-Like Cells","volume":"7","author":"Audia","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrc1590","article-title":"Tumour stem cells and drug resistance","volume":"5","author":"Dean","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/path.4349","article-title":"Endothelial cells promote stem-like phenotype of glioma cells through activating the Hedgehog pathway","volume":"234","author":"Yan","year":"2014","journal-title":"J. Pathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"11505","DOI":"10.1007\/s13277-014-2466-z","article-title":"LEF1 regulates glioblastoma cell proliferation, migration, invasion, and cancer stem-like cell self-renewal","volume":"35","author":"Gao","year":"2014","journal-title":"Tumor Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.2217\/nnm-2020-0256","article-title":"Extracellular vesicles in cancer progression: Are they part of the problem or part of the solution?","volume":"15","author":"Scholl","year":"2020","journal-title":"Nanomed"},{"key":"ref_55","first-page":"1470","article-title":"Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers","volume":"10","author":"Skog","year":"2008","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/labinvest.2017.19","article-title":"Immune microenvironment of gliomas","volume":"97","author":"Gieryng","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1158\/2159-8290.CD-20-1808","article-title":"Therapeutic Targeting of the Tumor Microenvironment","volume":"11","author":"Bejarano","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/imr.12529","article-title":"Co-inhibitory blockade while preserving tolerance: Checkpoint inhibitors for glioblastoma","volume":"276","author":"Lucca","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1158\/1078-0432.CCR-18-0047","article-title":"T-cell Dysfunction in Glioblastoma: Applying a New Framework","volume":"24","author":"Woroniecka","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e1448329","DOI":"10.1080\/2162402X.2018.1448329","article-title":"The immune checkpoint protein PD-L1 induces and maintains regulatory T cells in glioblastoma","volume":"7","author":"DiDomenico","year":"2018","journal-title":"OncoImmunology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41571-019-0175-7","article-title":"Regulatory T cells in cancer immunosuppression\u2014Implications for anticancer therapy","volume":"16","author":"Togashi","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3294","DOI":"10.1158\/0008-5472.CAN-05-3773","article-title":"Increased Regulatory T-Cell Fraction Amidst a Diminished CD4 Compartment Explains Cellular Immune Defects in Patients with Malignant Glioma","volume":"66","author":"Fecci","year":"2006","journal-title":"Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1007\/s12035-009-8063-2","article-title":"Purinoceptors on Neuroglia","volume":"39","author":"Verkhratsky","year":"2009","journal-title":"Mol. Neurobiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/nature13085","article-title":"Nucleotide signalling during inflammation","volume":"509","author":"Idzko","year":"2014","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.cell.2012.01.021","article-title":"Hypoxia-Inducible Factors in Physiology and Medicine","volume":"148","author":"Semenza","year":"2012","journal-title":"Cell"},{"key":"ref_66","first-page":"1","article-title":"Purine metabolism regulates DNA repair and therapy resistance in glioblastoma","volume":"11","author":"Zhou","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s11302-014-9427-2","article-title":"Purinergic signalling and immune cells","volume":"10","author":"Burnstock","year":"2014","journal-title":"Purinergic Signal."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.ccell.2019.10.007","article-title":"Adenosine Metabolism: Emerging Concepts for Cancer Therapy","volume":"36","author":"Boison","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"S172","DOI":"10.1038\/sj.bjp.0706429","article-title":"Purinergic signalling","volume":"147","author":"Burnstock","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1038\/onc.2012.269","article-title":"ENTPD1\/CD39 is a promising therapeutic target in oncology","volume":"32","author":"Bastid","year":"2012","journal-title":"Oncogene"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s11302-012-9309-4","article-title":"Cellular function and molecular structure of ecto-nucleotidases","volume":"8","author":"Zimmermann","year":"2012","journal-title":"Purinergic Signal."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s11302-018-9642-3","article-title":"Hydrolysis of ATP, ADP, and AMP is increased in blood plasma of prostate cancer patients","volume":"15","author":"Gardani","year":"2019","journal-title":"Purinergic Signal."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2012\/959848","article-title":"Ectonucleotidases in Tumor Cells and Tumor-Associated Immune Cells: An Overview","volume":"2012","author":"Bergamin","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6347","DOI":"10.1093\/emboj\/20.22.6347","article-title":"Proteomic and functional evidence for a P2X7 receptor signalling complex","volume":"20","author":"Kim","year":"2001","journal-title":"EMBO J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nrn1928","article-title":"Purinergic signalling in neuron\u2013glia interactions","volume":"7","author":"Fields","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1111\/bph.15005","article-title":"Update of P2Y receptor pharmacology: IUPHAR Review 27","volume":"177","author":"Jacobson","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1002\/wmts.62","article-title":"Coupling of P2Y receptors to G proteins and other signaling pathways","volume":"1","author":"Erb","year":"2012","journal-title":"Wiley Interdiscip. Rev. Membr. Transp. Signal."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1172\/JCI20986","article-title":"Central role of the P2Y12 receptor in platelet activation","volume":"113","author":"Dorsam","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"28795","DOI":"10.1074\/jbc.M801588200","article-title":"The Gi-coupled P2Y12 Receptor Regulates Diacylglycerol-mediated Signaling in Human Platelets","volume":"283","author":"Guidetti","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1182\/blood-2004-02-0534","article-title":"Reciprocal cross-talk between P2Y1 and P2Y12 receptors at the level of calcium signaling in human platelets","volume":"104","author":"Hardy","year":"2004","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1055\/s-0037-1615690","article-title":"Potentiation of thromboxane A2-induced platelet secretion by Gi signaling through the phosphoinositide-3 kinase pathway","volume":"85","author":"Dangelmaier","year":"2001","journal-title":"Thromb. Haemost."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12032-013-0567-y","article-title":"P2Y12 receptor inhibition augments cytotoxic effects of cisplatin in breast cancer","volume":"30","author":"Sarangi","year":"2013","journal-title":"Med. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/sj.bjp.0705639","article-title":"Differential effects of P2Y1 and P2Y12 nucleotide receptors on ERK1\/ERK2 and phosphatidylinositol 3-kinase signalling and cell proliferation in serum-deprived and nonstarved glioma C6 cells","volume":"141","author":"Czajkowski","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"119612","DOI":"10.1016\/j.lfs.2021.119612","article-title":"Activated platelets contribute to the progression of hepatocellular carcinoma by altering the tumor environment","volume":"277","author":"Kopsida","year":"2021","journal-title":"Life Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"617211","DOI":"10.3389\/fphar.2020.617211","article-title":"Extracellular ATP Mediates Cancer Cell Migration and Invasion Through Increased Expression of Cyclooxygenase 2","volume":"11","author":"Sharma","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.18632\/aging.202269","article-title":"Immune profile of the tumor microenvironment and the identification of a four-gene signature for lung adenocarcinoma","volume":"13","author":"Fan","year":"2021","journal-title":"Aging"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.mcn.2009.08.010","article-title":"Role of VASP phosphorylation for the regulation of microglia chemotaxis via the regulation of focal adhesion formation\/maturation","volume":"42","author":"Lee","year":"2009","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3749","DOI":"10.1021\/jm400422s","article-title":"Structure-Based Approaches to Ligands for G-Protein-Coupled Adenosine and P2Y Receptors, from Small Molecules to Nanoconjugates","volume":"56","author":"Jacobson","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.ccr.2013.05.008","article-title":"Platelet-Derived Nucleotides Promote Tumor-Cell Transendothelial Migration and Metastasis via P2Y2 Receptor","volume":"24","author":"Schumacher","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1002\/ijc.28947","article-title":"The reversible P2Y12 inhibitor ticagrelor inhibits metastasis and improves survival in mouse models of cancer","volume":"136","author":"Gebremeskel","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1158\/0008-5472.CAN-04-3376","article-title":"PTEN and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation by Glioblastoma","volume":"65","author":"Rong","year":"2005","journal-title":"Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3544","DOI":"10.1073\/pnas.1314118111","article-title":"Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations","volume":"111","author":"Magnus","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1159\/000093551","article-title":"Mechanisms of Cancer-Induced Thrombosis in Cancer","volume":"35","author":"Rickles","year":"2006","journal-title":"Pathophysiol. Haemost. Thromb."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"315","DOI":"10.3892\/ol.2016.4593","article-title":"Hypoxia regulates the expression of tissue factor pathway signaling elements in a rat glioma model","volume":"12","author":"Monteiro","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.ccr.2011.09.009","article-title":"Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis","volume":"20","author":"Labelle","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Vollmann-Zwerenz, A., Leidgens, V., Feliciello, G., Klein, C.A., and Hau, P. (2020). Tumor Cell Invasion in Glioblastoma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21061932"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"90488","DOI":"10.18632\/oncotarget.21799","article-title":"A relative increase in circulating platelets following chemoradiation predicts for poor survival of patients with glioblastoma","volume":"8","author":"Boonyawan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Chang, C.-Y., Pan, P.-H., Li, J.-R., Ou, Y.-C., Wang, J.-D., Liao, S.-L., Chen, W.-Y., Wang, W.-Y., and Chen, C.-J. (2020). Aspirin Induced Glioma Apoptosis through Noxa Upregulation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124219"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.18632\/aging.101224","article-title":"Aspirin inhibits the SHH\/GLI1 signaling pathway and sensitizes malignant glioma cells to temozolomide therapy","volume":"9","author":"Ming","year":"2017","journal-title":"Aging"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.amjmed.2017.01.022","article-title":"The Effect of Combined Aspirin and Clopidogrel Treatment on Cancer Incidence","volume":"130","author":"Leader","year":"2017","journal-title":"Am. J. Med."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Marx, S., Xiao, Y., Baschin, M., Splittst\u00f6hser, M., Altmann, R., Moritz, E., Jedlitschky, G., Bien-M\u00f6ller, S., Schroeder, H.W., and Rauch, B.H. (2019). The Role of Platelets in Cancer Pathophysiology: Focus on Malignant Glioma. Cancers, 11.","DOI":"10.3390\/cancers11040569"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.3389\/fimmu.2019.01805","article-title":"Platelets, Thrombo-Inflammation, and Cancer: Collaborating with the Enemy","volume":"10","author":"Crescence","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s10143-011-0320-y","article-title":"Cytokine networks in glioma","volume":"34","author":"Iwami","year":"2011","journal-title":"Neurosurg. Rev."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/978-94-007-4719-7_9","article-title":"TGF Beta Signaling and Its Role in Glioma Pathogenesis","volume":"986","author":"Kaminska","year":"2013","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1182\/blood-2007-09-113837","article-title":"Angiogenesis is regulated by a novel mechanism: Pro- and antiangiogenic proteins are organized into separate platelet \u03b1 granules and differentially released","volume":"111","author":"Italiano","year":"2008","journal-title":"Blood"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1016\/j.bcp.2003.12.017","article-title":"Reactive blue 2 inhibition of cyclic AMP-dependent differentiation of rat C6 glioma cells by purinergic receptor-independent inactivation of phosphatidylinositol 3-kinase","volume":"67","author":"Claes","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1111\/j.1471-4159.2004.02339.x","article-title":"P2Y12receptor stimulation inhibits?-adrenergic receptor-induced differentiation by reversing the cyclic AMP-dependent inhibition of protein kinase B","volume":"89","author":"Slegers","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"477","DOI":"10.3171\/jns.1977.46.4.0477","article-title":"Cyclic AMP and adenyl cyclase in brain tumors","volume":"46","author":"Furman","year":"1977","journal-title":"J. Neurosurg."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"e46912","DOI":"10.7554\/eLife.46912","article-title":"Brain tumours repurpose endogenous neuron to microglia signalling mechanisms to promote their own proliferation","volume":"8","author":"Chia","year":"2019","journal-title":"eLife"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.neuropharm.2015.12.001","article-title":"Medicinal chemistry of adenosine, P2Y and P2X receptors","volume":"104","author":"Jacobson","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Bara\u0144ska, J. (2020). Cross-Talk in Nucleotide Signaling in Glioma C6 Cells. Glioma Signal, Springer International Publishing.","DOI":"10.1007\/978-3-030-30651-9"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.ccell.2015.08.012","article-title":"Dual Targeting of the Autophagic Regulatory Circuitry in Gliomas with Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit","volume":"28","author":"Shchors","year":"2015","journal-title":"Cancer Cell"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/20\/6146\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:11:59Z","timestamp":1760166719000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/20\/6146"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,12]]},"references-count":112,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["molecules26206146"],"URL":"https:\/\/doi.org\/10.3390\/molecules26206146","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,12]]}}}