{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T19:05:11Z","timestamp":1783105511671,"version":"3.54.6"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T00:00:00Z","timestamp":1684108800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T00:00:00Z","timestamp":1684108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["88887.338883\/2019-00"],"award-info":[{"award-number":["88887.338883\/2019-00"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Med Oncol"],"DOI":"10.1007\/s12032-023-02033-6","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T18:02:28Z","timestamp":1684173748000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Istradefylline induces A2A\/P2X7 crosstalk expression inducing pro-inflammatory signal, and reduces AKT\/mTOR signaling in melanoma-bearing mice"],"prefix":"10.1007","volume":"40","author":[{"given":"Jean L.","family":"Gutknecht da Silva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela F.","family":"Passos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda L.","family":"Cabral","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa V.","family":"Miron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria R. C.","family":"Schetinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrieli A.","family":"Cardoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camile H.","family":"Dal Piva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina O.","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renan S.","family":"Ebone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2618-9801","authenticated-orcid":false,"given":"Daniela B. R.","family":"Leal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,15]]},"reference":[{"key":"2033_CR1","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/onc.2016.206","volume":"36","author":"F Di Virgilio","year":"2017","unstructured":"Di Virgilio F, Adinolfi E. Extracellular purines, purinergic receptors and tumor growth. Oncog Nat Publ Gr. 2017;36:293\u2013303.","journal-title":"Oncog Nat Publ Gr"},{"key":"2033_CR2","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1158\/2159-8290.CD-19-0541","volume":"9","author":"X-Y Li","year":"2019","unstructured":"Li X-Y, Moesta AK, Xiao C, Nakamura K, Casey M, Zhang H, et al. Targeting CD39 in cancer reveals an extracellular ATP- and inflammasome-driven tumor immunity. Cancer Discov. 2019;9:1754\u201373. https:\/\/doi.org\/10.1158\/2159-8290.CD-19-0541.","journal-title":"Cancer Discov"},{"key":"2033_CR3","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1111\/imr.12528","volume":"276","author":"B Allard","year":"2017","unstructured":"Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD 39 and CD 73: novel checkpoint inhibitor targets. Immunol Rev. 2017;276:121\u201344.","journal-title":"Immunol Rev"},{"key":"2033_CR4","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1046\/j.1471-4159.2001.00607.x","volume":"79","author":"S Latini","year":"2001","unstructured":"Latini S, Pedata F. Adenosine in the central nervous system: release mechanisms and extracellular concentrations. J Neurochem. 2001;79:463\u201384. https:\/\/doi.org\/10.1046\/j.1471-4159.2001.00607.x.","journal-title":"J Neurochem"},{"key":"2033_CR5","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1038\/s41571-020-0382-2","volume":"17","author":"B Allard","year":"2020","unstructured":"Allard B, Allard D, Buisseret L, Stagg J. The adenosine pathway in immuno-oncology. Nat Rev Clin Oncol. 2020;17:611\u201329. https:\/\/doi.org\/10.1038\/s41571-020-0382-2.","journal-title":"Nat Rev Clin Oncol"},{"key":"2033_CR6","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1016\/j.bbamem.2010.12.017","volume":"1808","author":"CE M\u00fcller","year":"2011","unstructured":"M\u00fcller CE, Jacobson KA. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta\u2014Biomembr. 2011;1808:1290\u2013308.","journal-title":"Biochim Biophys Acta\u2014Biomembr"},{"key":"2033_CR7","first-page":"33","volume-title":"Adenosine recept","author":"S Merighi","year":"2018","unstructured":"Merighi S, Gessi S, Borea PA. Adenosine receptors: structure, distribution, and signal transduction. In: Borea PA, Varani K, Gessi S, Merighi S, Vincenzi F, editors. Adenosine recept. Cham: Springer; 2018. p. 33\u201357."},{"key":"2033_CR8","doi-asserted-by":"publisher","first-page":"7250","DOI":"10.1158\/0008-5472.CAN-13-3583","volume":"74","author":"C Cekic","year":"2014","unstructured":"Cekic C, Day Y-J, Sag D, Linden J. Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment. Cancer Res AACR. 2014;74:7250\u20139.","journal-title":"Cancer Res AACR"},{"key":"2033_CR9","doi-asserted-by":"publisher","first-page":"190","DOI":"10.3389\/fimmu.2012.00190","volume":"3","author":"A Ohta","year":"2012","unstructured":"Ohta A, Kini R, Ohta A, Subramanian M, Madasu M, Sitkovsky M. The development and immunosuppressive functions of CD4+ CD25+ FoxP3+ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front Immunol. 2012;3:190.","journal-title":"Front Immunol"},{"key":"2033_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13045-019-0724-7","volume":"12","author":"X-L Ma","year":"2019","unstructured":"Ma X-L, Shen M-N, Hu B, Wang B-L, Yang W-J, Lv L-H, et al. CD73 promotes hepatocellular carcinoma progression and metastasis via activating PI3K\/AKT signaling by inducing Rap1-mediated membrane localization of P110\u03b2 and predicts poor prognosis. J Hematol Oncol. 2019;12:1\u201317.","journal-title":"J Hematol Oncol"},{"key":"2033_CR11","doi-asserted-by":"publisher","first-page":"1831","DOI":"10.1038\/onc.2014.113","volume":"34","author":"JZ Zhou","year":"2015","unstructured":"Zhou JZ, Riquelme MA, Gao X, Ellies LG, Sun L-Z, Jiang JX. Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis. Oncog Nat. 2015;34:1831\u201342.","journal-title":"Oncog Nat"},{"key":"2033_CR12","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1007\/s40265-013-0066-7","volume":"73","author":"R Dungo","year":"2013","unstructured":"Dungo R, Deeks ED. Istradefylline: first global approval. Drugs. 2013;73:875\u201382.","journal-title":"Drugs"},{"key":"2033_CR13","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/S1474-4422(14)70148-6","volume":"13","author":"RA Hauser","year":"2014","unstructured":"Hauser RA, Olanow CW, Kieburtz KD, Pourcher E, Docu-Axelerad A, Lew M, et al. Tozadenant (SYN115) in patients with Parkinson\u2019s disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol. 2014;13:767\u201376.","journal-title":"Lancet Neurol"},{"key":"2033_CR14","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/591094","author":"CJ Bleickardt","year":"2012","unstructured":"Bleickardt CJ, LaShomb AL, Merkel CE, Hodgson RA. Adenosine A2A receptor antagonists do not disrupt rodent prepulse inhibition: an improved side effect profile in the treatment of parkinson\u2019s disease. Parkinson\u2019s Dis. 2012. https:\/\/doi.org\/10.1155\/2012\/591094.","journal-title":"Parkinson\u2019s Dis"},{"key":"2033_CR15","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1002\/cbf.3616","volume":"39","author":"PH Doleski","year":"2021","unstructured":"Doleski PH, Cabral FL, Adefegha SA, Jantsch MH, Ebone RS, Leal DBR, et al. Distinct kinetics for nucleotide hydrolysis in lymphocytes isolated from blood, spleen and cervical lymph nodes: Characterization of ectonucleotidase activity. Cell Biochem Funct. 2021;39:511\u201320.","journal-title":"Cell Biochem Funct"},{"key":"2033_CR16","first-page":"93","volume-title":"Mouse model innate immun methods protoc","author":"YS Tan","year":"2019","unstructured":"Tan YS, Lei YL. Isolation of tumor-infiltrating lymphocytes by ficoll-paque density gradient centrifugation. In: Allen IC, editor. Mouse model innate immun methods protoc. Springer: New York; 2019. p. 93\u20139."},{"key":"2033_CR17","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","volume":"72","author":"MM Bradford","year":"1976","unstructured":"Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248\u201354.","journal-title":"Anal Biochem"},{"key":"2033_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-091302-2.50108-0","author":"GGB Giusti","year":"1984","unstructured":"Giusti GGB. Adenosine deaminase. Methods Enzym Anal. 1984. https:\/\/doi.org\/10.1016\/B978-0-12-091302-2.50108-0.","journal-title":"Methods Enzym Anal"},{"key":"2033_CR19","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/0003-2697(86)90640-8","volume":"157","author":"KM Chan","year":"1986","unstructured":"Chan KM, Delfert D, Junger KD. A direct colorimetric assay for Ca2+-stimulated ATPase activity. Anal Biochem. 1986;157:375\u201380.","journal-title":"Anal Biochem"},{"key":"2033_CR20","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.clim.2003.11.017","volume":"110","author":"E Morgan","year":"2004","unstructured":"Morgan E, Varro R, Sepulveda H, Ember JA, Apgar J, Wilson J, et al. Cytometric bead array: a multiplexed assay platform with applications in various areas of biology. Clin Immunol. 2004;110:252\u201366.","journal-title":"Clin Immunol"},{"key":"2033_CR21","doi-asserted-by":"publisher","DOI":"10.1007\/s11302-022-09909-8","author":"JLG da Silva","year":"2022","unstructured":"da Silva JLG, Viana AR, Passos DF, Krause LMF, Miron VV, Schetinger MRC, et al. Istradefylline modulates purinergic enzymes and reduces malignancy-associated factors in B16F10 melanoma cells. Purinergic Signal. 2022. https:\/\/doi.org\/10.1007\/s11302-022-09909-8.","journal-title":"Purinergic Signal"},{"key":"2033_CR22","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1016\/j.immuni.2013.10.010","volume":"39","author":"V Bronte","year":"2013","unstructured":"Bronte V, Pittet MJ. The spleen in local and systemic regulation of immunity. Immunity. 2013;39:806\u201318.","journal-title":"Immunity"},{"key":"2033_CR23","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/B978-0-12-385526-8.00009-6","volume-title":"Pharmacol purine pyrimidine recept","author":"F Kukulski","year":"2011","unstructured":"Kukulski F, L\u00e9vesque SA, S\u00e9vigny J. Chapter 9\u2014Impact of ectoenzymes on P2 and P1 receptor signaling. In: Jacobson KA, Linden JBT-A, editors. Pharmacol purine pyrimidine recept. Cambridge: Academic Press; 2011. p. 263\u201399."},{"key":"2033_CR24","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.thromres.2007.04.008","volume":"121","author":"ED Pulte","year":"2007","unstructured":"Pulte ED, Broekman MJ, Olson KE, Drosopoulos JHF, Kizer JR, Islam N, et al. CD39\/NTPDase-1 activity and expression in normal leukocytes. Thromb Res. 2007;121:309\u201317.","journal-title":"Thromb Res"},{"key":"2033_CR25","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/nri2938","volume":"11","author":"WG Junger","year":"2011","unstructured":"Junger WG. Immune cell regulation by autocrine purinergic signalling. Nat Rev Immunol. 2011;11:201.","journal-title":"Nat Rev Immunol"},{"key":"2033_CR26","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00793","author":"R Lara","year":"2020","unstructured":"Lara R, Adinolfi E, Harwood CA, Philpott M, Barden JA, Di Virgilio F, et al. P2X7 in cancer: from molecular mechanisms to therapeutics. Front Pharmacol. 2020. https:\/\/doi.org\/10.3389\/fphar.2020.00793.","journal-title":"Front Pharmacol"},{"key":"2033_CR27","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1080\/17460441.2018.1534825","volume":"13","author":"M Congreve","year":"2018","unstructured":"Congreve M, Brown GA, Borodovsky A, Lamb ML. Targeting adenosine A2A receptor antagonism for treatment of cancer. Expert Opin Drug Discov. 2018;13:997\u20131003. https:\/\/doi.org\/10.1080\/17460441.2018.1534825.","journal-title":"Expert Opin Drug Discov"},{"key":"2033_CR28","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.876510","author":"E De Marchi","year":"2022","unstructured":"De Marchi E, Pegoraro A, Turiello R, Di Virgilio F, Morello S, Adinolfi E. A2A Receptor contributes to tumor progression in P2X7 null mice. bioRxiv. 2022. https:\/\/doi.org\/10.3389\/fcell.2022.876510.","journal-title":"bioRxiv"},{"key":"2033_CR29","doi-asserted-by":"publisher","first-page":"2261","DOI":"10.2174\/0929867324666170303161659","volume":"24","author":"E Orioli","year":"2017","unstructured":"Orioli E, De Marchi E, Lisa Giuliani A, Adinolfi E. P2X7 receptor orchestrates multiple signalling pathways triggering inflammation, autophagy and metabolic\/trophic responses. Curr Med Chem. 2017;24:2261\u201375.","journal-title":"Curr Med Chem"},{"key":"2033_CR30","doi-asserted-by":"publisher","first-page":"787","DOI":"10.4049\/jimmunol.0901363","volume":"183","author":"FG Bauernfeind","year":"2009","unstructured":"Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-\u03baB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787\u201391.","journal-title":"J Immunol"},{"key":"2033_CR31","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/nri.2016.80","volume":"16","author":"DE Speiser","year":"2016","unstructured":"Speiser DE, Ho P-C, Verdeil G. Regulatory circuits of T cell function in cancer. Nat Rev Immunol. 2016;16:599\u2013611. https:\/\/doi.org\/10.1038\/nri.2016.80.","journal-title":"Nat Rev Immunol"},{"key":"2033_CR32","doi-asserted-by":"publisher","first-page":"14711","DOI":"10.1073\/pnas.1308209110","volume":"110","author":"PA Beavis","year":"2013","unstructured":"Beavis PA, Divisekera U, Paget C, Chow MT, John LB, Devaud C, et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc Natl Acad Sci USA. 2013;110:14711\u20136.","journal-title":"Proc Natl Acad Sci USA"},{"key":"2033_CR33","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1084\/jem.173.4.869","volume":"173","author":"SH Chan","year":"1991","unstructured":"Chan SH, Perussia B, Gupta JW, Kobayashi M, Posp\u00edsil M, Young HA, et al. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med. 1991;173:869\u201379. https:\/\/doi.org\/10.1084\/jem.173.4.869.","journal-title":"J Exp Med"},{"key":"2033_CR34","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1016\/j.ccr.2011.11.003","volume":"20","author":"JB Mumm","year":"2011","unstructured":"Mumm JB, Emmerich J, Zhang X, Chan I, Wu L, Mauze S, et al. IL-10 elicits IFN\u03b3-dependent tumor immune surveillance. Cancer Cell. 2011;20:781\u201396.","journal-title":"Cancer Cell"},{"key":"2033_CR35","doi-asserted-by":"publisher","first-page":"2143","DOI":"10.1182\/blood.V98.7.2143","volume":"98","author":"S Fujii","year":"2001","unstructured":"Fujii S, Shimizu K, Shimizu T, Lotze MT. Interleukin-10 promotes the maintenance of antitumor CD8+ T-cell effector function in situ. Blood. 2001;98:2143\u201351. https:\/\/doi.org\/10.1182\/blood.V98.7.2143.","journal-title":"Blood"},{"key":"2033_CR36","doi-asserted-by":"publisher","first-page":"e984547","DOI":"10.4161\/2162402X.2014.984547","volume":"4","author":"S Punt","year":"2015","unstructured":"Punt S, Langenhoff JM, Putter H, Fleuren GJ, Gorter A, Jordanova ES. The correlations between IL-17 vs. Th17 cells and cancer patient survival: a systematic review. Oncoimmunology. 2015;4:e984547. https:\/\/doi.org\/10.4161\/2162402X.2014.984547.","journal-title":"Oncoimmunology"},{"key":"2033_CR37","doi-asserted-by":"publisher","DOI":"10.4110\/in.2020.20.e6","author":"D-S Kuen","year":"2020","unstructured":"Kuen D-S, Kim B-S, Chung Y. IL-17-producing cells in tumor immunity: friends or foes? Immune Netw. 2020. https:\/\/doi.org\/10.4110\/in.2020.20.e6.","journal-title":"Immune Netw"},{"key":"2033_CR38","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1016\/j.cell.2013.09.031","volume":"155","author":"G He","year":"2013","unstructured":"He G, Dhar D, Nakagawa H, Font-Burgada J, Ogata H, Jiang Y, et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell. 2013;155:384\u201396.","journal-title":"Cell"},{"key":"2033_CR39","doi-asserted-by":"publisher","first-page":"R79","DOI":"10.1186\/bcr3473","volume":"15","author":"K Oh","year":"2013","unstructured":"Oh K, Lee O-Y, Shon SY, Nam O, Ryu PM, Seo MW, et al. A mutual activation loop between breast cancer cells and myeloid-derived suppressor cells facilitates spontaneous metastasis through IL-6 trans-signaling in a murine model. Breast Cancer Res. 2013;15:R79. https:\/\/doi.org\/10.1186\/bcr3473.","journal-title":"Breast Cancer Res"},{"key":"2033_CR40","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.smim.2014.01.007","volume":"26","author":"Q Chang","year":"2014","unstructured":"Chang Q, Daly L, Bromberg J. The IL-6 feed-forward loop: a driver of tumorigenesis. Semin Immunol. 2014;26:48\u201353.","journal-title":"Semin Immunol"},{"key":"2033_CR41","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1083\/jcb.106.3.657","volume":"106","author":"F Di Virgilio","year":"1988","unstructured":"Di Virgilio F, Meyer BC, Greenberg S, Silverstein SC. Fc receptor-mediated phagocytosis occurs in macrophages at exceedingly low cytosolic Ca2+ levels. J Cell Biol. 1988;106:657\u201366. https:\/\/doi.org\/10.1083\/jcb.106.3.657.","journal-title":"J Cell Biol"},{"key":"2033_CR42","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.694831","author":"F Grassi","year":"2021","unstructured":"Grassi F, De Ponte CB. The P2X7 receptor in tumor immunity. Front Cell Dev Biol. 2021. https:\/\/doi.org\/10.3389\/fcell.2021.694831.","journal-title":"Front Cell Dev Biol"},{"key":"2033_CR43","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2015.00262","author":"B-Z Shao","year":"2015","unstructured":"Shao B-Z, Xu Z-Q, Han B-Z, Su D-F, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015. https:\/\/doi.org\/10.3389\/fphar.2015.00262.","journal-title":"Front Pharmacol"},{"key":"2033_CR44","doi-asserted-by":"publisher","first-page":"2527","DOI":"10.1091\/mbc.E19-03-0136","volume":"30","author":"L Shi","year":"2019","unstructured":"Shi L, Wu Z, Miao J, Du S, Ai S, Xu E, et al. Adenosine interaction with adenosine receptor A2a promotes gastric cancer metastasis by enhancing PI3K\u2013AKT\u2013mTOR signaling. Mol Biol Cell. 2019;30:2527\u201334. https:\/\/doi.org\/10.1091\/mbc.E19-03-0136.","journal-title":"Mol Biol Cell"},{"key":"2033_CR45","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1146\/annurev.cellbio.17.1.615","volume":"17","author":"R Katso","year":"2001","unstructured":"Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, immunity, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2001;17:615\u201375. https:\/\/doi.org\/10.1146\/annurev.cellbio.17.1.615.","journal-title":"Annu Rev Cell Dev Biol"},{"key":"2033_CR46","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1158\/1535-7163.MCT-17-0927","volume":"17","author":"S Xu","year":"2018","unstructured":"Xu S, Yang Z, Jin P, Yang X, Li X, Wei X, et al. Metformin suppresses tumor progression by inactivating stromal fibroblasts in ovarian cancer. Mol Cancer Ther. 2018;17:1291\u2013302. https:\/\/doi.org\/10.1158\/1535-7163.MCT-17-0927.","journal-title":"Mol Cancer Ther"},{"key":"2033_CR47","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1254\/jphs.10244FP","volume":"115","author":"T Yasuda","year":"2011","unstructured":"Yasuda T. Hyaluronan inhibits Akt, leading to nuclear factor-<I>&kappa;<\/I>B down-regulation in lipopolysaccharide-stimulated U937 macrophages. J Pharmacol Sci. 2011;115:509\u201315.","journal-title":"J Pharmacol Sci"},{"key":"2033_CR48","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/sj.leu.2404523","volume":"21","author":"PL Tazzari","year":"2007","unstructured":"Tazzari PL, Cappellini A, Ricci F, Evangelisti C, Papa V, Grafone T, et al. Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase\/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia. 2007;21:427\u201338. https:\/\/doi.org\/10.1038\/sj.leu.2404523.","journal-title":"Leukemia"},{"key":"2033_CR49","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1038\/s41419-018-0849-6","volume":"9","author":"MW Usman","year":"2018","unstructured":"Usman MW, Gao J, Zheng T, Rui C, Li T, Bian X, et al. Macrophages confer resistance to PI3K inhibitor GDC-0941 in breast cancer through the activation of NF-\u03baB signaling. Cell Death Dis. 2018;9:809. https:\/\/doi.org\/10.1038\/s41419-018-0849-6.","journal-title":"Cell Death Dis"},{"key":"2033_CR50","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00054","author":"C Giacomelli","year":"2018","unstructured":"Giacomelli C, Daniele S, Romei C, Tavanti L, Neri T, Piano I, et al. The A2B adenosine receptor modulates the epithelial\u2014mesenchymal transition through the balance of cAMP\/PKA and MAPK\/ERK pathway activation in human epithelial lung cells. Front Pharmacol. 2018. https:\/\/doi.org\/10.3389\/fphar.2018.00054.","journal-title":"Front Pharmacol"},{"key":"2033_CR51","doi-asserted-by":"publisher","first-page":"888","DOI":"10.3389\/fphar.2017.00888","volume":"8","author":"S Gessi","year":"2017","unstructured":"Gessi S, Bencivenni S, Battistello E, Vincenzi F, Colotta V, Catarzi D, et al. Inhibition of A2A adenosine receptor signaling in cancer cells proliferation by the novel antagonist TP455. Front Pharmacol. 2017;8:888.","journal-title":"Front Pharmacol"},{"key":"2033_CR52","doi-asserted-by":"publisher","first-page":"6074","DOI":"10.1158\/0008-5472.CAN-21-3605","volume":"81","author":"JS Bergholz","year":"2021","unstructured":"Bergholz JS, Zhao JJ. How compensatory mechanisms and adaptive rewiring have shaped our understanding of therapeutic resistance in cancer. Cancer Res. 2021;81:6074\u20137. https:\/\/doi.org\/10.1158\/0008-5472.CAN-21-3605.","journal-title":"Cancer Res"},{"key":"2033_CR53","doi-asserted-by":"publisher","first-page":"3065","DOI":"10.1172\/JCI34739","volume":"118","author":"A Carracedo","year":"2008","unstructured":"Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118:3065\u201374. https:\/\/doi.org\/10.1172\/JCI34739.","journal-title":"J Clin Invest"}],"container-title":["Medical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12032-023-02033-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12032-023-02033-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12032-023-02033-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T02:30:37Z","timestamp":1685068237000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12032-023-02033-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,15]]},"references-count":53,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["2033"],"URL":"https:\/\/doi.org\/10.1007\/s12032-023-02033-6","relation":{},"ISSN":["1559-131X"],"issn-type":[{"value":"1559-131X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,15]]},"assertion":[{"value":"9 March 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 April 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 May 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors have no conflicts of interest to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This project was approved by the Animals Use Ethics Commission of Universidade Federal de Santa Maria (CEUA\/UFSM). The approval was granted under protocol number 4748290420.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval"}},{"value":"All authors have seen and agreed with the content and given consent to submit\u00a0the manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"178"}}