{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:47:51Z","timestamp":1790225271943,"version":"4.1.0"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:00:00Z","timestamp":1680480000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:00:00Z","timestamp":1680480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MRCCRTF11-8"],"award-info":[{"award-number":["MRCCRTF11-8"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015652","name":"Barts Charity","doi-asserted-by":"publisher","award":["MRD0240"],"award-info":[{"award-number":["MRD0240"]}],"id":[{"id":"10.13039\/100015652","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015652","name":"Barts Charity","doi-asserted-by":"publisher","award":["006836 QM"],"award-info":[{"award-number":["006836 QM"]}],"id":[{"id":"10.13039\/100015652","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C12522\/A8632"],"award-info":[{"award-number":["C12522\/A8632"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pharmacol. Rep"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Pegylated arginine deiminase (ADI-PEG20; pegargiminase) depletes arginine and improves survival outcomes for patients with argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). Optimisation of ADI-PEG20-based therapy will require a deeper understanding of resistance mechanisms, including those mediated by the tumor microenvironment. Here, we sought to reverse translate increased tumoral macrophage infiltration in patients with ASS1-deficient MPM relapsing on pegargiminase therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Macrophage-MPM tumor cell line (2591, MSTO, JU77) co-cultures treated with ADI-PEG20 were analyzed by flow cytometry. Microarray experiments of gene expression profiling were performed in ADI-PEG20-treated MPM tumor cells, and macrophage-relevant genetic \u201chits\u201d were validated by qPCR, ELISA, and LC\/MS. Cytokine and argininosuccinate analyses were performed using plasma from pegargiminase-treated patients with MPM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified that ASS1-expressing macrophages promoted viability of ADI-PEG20-treated ASS1-negative MPM cell lines. Microarray gene expression data revealed a dominant CXCR2-dependent chemotactic signature and co-expression of VEGF-A and IL-1\u03b1 in ADI-PEG20-treated MPM cell lines. We confirmed that ASS1 in macrophages was IL-1\u03b1-inducible and that the argininosuccinate concentration doubled in the cell supernatant sufficient to restore MPM cell viability under co-culture conditions with ADI-PEG20. For further validation, we detected elevated plasma VEGF-A and CXCR2-dependent cytokines, and increased argininosuccinate in patients with MPM progressing on ADI-PEG20. Finally, liposomal clodronate depleted ADI-PEG20-driven macrophage infiltration and suppressed growth significantly in the MSTO xenograft murine model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Collectively, our data indicate that ADI-PEG20-inducible cytokines orchestrate argininosuccinate fuelling of ASS1-deficient mesothelioma by macrophages. This novel stromal-mediated resistance pathway may be leveraged to optimize arginine deprivation therapy for mesothelioma and related arginine-dependent cancers.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s43440-023-00480-6","type":"journal-article","created":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T10:42:45Z","timestamp":1680518565000},"page":"570-584","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma"],"prefix":"10.1007","volume":"75","author":[{"given":"Melissa M.","family":"Phillips","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iuliia","family":"Pavlyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Essam","family":"Ghazaly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalind","family":"Cutts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josephine","family":"Carpentier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe Scott","family":"Berry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Callum","family":"Nattress","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenghui","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnel","family":"Hallden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Chelala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Bomalaski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Steele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Sheaff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Balkwill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5039-711X","authenticated-orcid":false,"given":"Peter W.","family":"Szlosarek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,4,3]]},"reference":[{"issue":"6","key":"480_CR1","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.1002\/ijc.32931","volume":"147","author":"E Sirri","year":"2020","unstructured":"Sirri E, Kieschke J, Vohmann C, Katalinic A, Nennecke A, Ressing M, et al. Survival of malignant mesothelioma and other rare thoracic cancers in Germany and the United States: a population-based study. Int J Cancer. 2020;147(6):1548\u201358.","journal-title":"Int J Cancer"},{"key":"480_CR2","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.cllc.2020.11.009","volume":"22","author":"D Uprety","year":"2022","unstructured":"Uprety D. CheckMate 743: a glimmer of hope for malignant pleural mesothelioma. Clin Lung Cancer. 2022;22:71\u20133.","journal-title":"Clin Lung Cancer"},{"issue":"14","key":"480_CR3","doi-asserted-by":"publisher","first-page":"2636","DOI":"10.1200\/JCO.2003.11.136","volume":"21","author":"NJ Vogelzang","year":"2003","unstructured":"Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636\u201344.","journal-title":"J Clin Oncol"},{"issue":"10272","key":"480_CR4","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/S0140-6736(20)32714-8","volume":"397","author":"P Baas","year":"2021","unstructured":"Baas P, Scherpereel A, Nowak AK, Fujimoto N, Peters S, Tsao AS, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021;397(10272):375\u201386.","journal-title":"Lancet"},{"issue":"4","key":"480_CR5","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1080\/14737140.2020.1745067","volume":"20","author":"N van Zandwijk","year":"2020","unstructured":"van Zandwijk N, Reid G, Frank AL. Asbestos-related cancers: the \u201cHidden Killer\u201d remains a global threat. Expert Rev Anticancer Ther. 2020;20(4):271\u20138.","journal-title":"Expert Rev Anticancer Ther"},{"issue":"23","key":"480_CR6","doi-asserted-by":"publisher","first-page":"7126","DOI":"10.1158\/1078-0432.CCR-06-1101","volume":"12","author":"PW Szlosarek","year":"2006","unstructured":"Szlosarek PW, Klabatsa A, Pallaska A, Sheaff M, Smith P, Crook T, et al. In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion. Clin Cancer Res. 2006;12(23):7126\u201331.","journal-title":"Clin Cancer Res"},{"issue":"4","key":"480_CR7","doi-asserted-by":"publisher","first-page":"251","DOI":"10.4143\/crt.2013.45.4.251","volume":"45","author":"MM Phillips","year":"2013","unstructured":"Phillips MM, Sheaff MT, Szlosarek PW. Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges. Cancer Res Treat. 2013;45(4):251\u201362.","journal-title":"Cancer Res Treat"},{"issue":"9","key":"480_CR8","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.1046\/j.1432-1033.2003.03559.x","volume":"270","author":"A Husson","year":"2003","unstructured":"Husson A, Brasse-Lagnel C, Fairand A, Renouf S, Lavoinne A. Argininosuccinate synthetase from the urea cycle to the citrulline-NO cycle. European journal of biochemistry \/ FEBS. 2003;270(9):1887\u201399.","journal-title":"European journal of biochemistry \/ FEBS"},{"issue":"12","key":"480_CR9","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.1002\/ijc.25202","volume":"126","author":"B Delage","year":"2010","unstructured":"Delage B, Fennell DA, Nicholson L, McNeish I, Lemoine NR, Crook T, et al. Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int J Cancer. 2010;126(12):2762\u201372.","journal-title":"Int J Cancer"},{"issue":"10","key":"480_CR10","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1038\/s41568-018-0054-z","volume":"18","author":"R Keshet","year":"2018","unstructured":"Keshet R, Szlosarek P, Carracedo A, Erez A. Rewiring urea cycle metabolism in cancer to support anabolism. Nat Rev Cancer. 2018;18(10):634\u201345.","journal-title":"Nat Rev Cancer"},{"issue":"3","key":"480_CR11","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1158\/0008-5472.CAN-13-1702","volume":"74","author":"MD Allen","year":"2014","unstructured":"Allen MD, Luong P, Hudson C, Leyton J, Delage B, Ghazaly E, et al. Prognostic and therapeutic impact of argininosuccinate synthetase 1 control in bladder cancer as monitored longitudinally by PET imaging. Cancer Res. 2014;74(3):896\u2013907.","journal-title":"Cancer Res"},{"issue":"7578","key":"480_CR12","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1038\/nature15529","volume":"527","author":"S Rabinovich","year":"2015","unstructured":"Rabinovich S, Adler L, Yizhak K, Sarver A, Silberman A, Agron S, et al. Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis. Nature. 2015;527(7578):379\u201383.","journal-title":"Nature"},{"issue":"19","key":"480_CR13","first-page":"5443","volume":"62","author":"CM Ensor","year":"2002","unstructured":"Ensor CM, Holtsberg FW, Bomalaski JS, Clark MA. Pegylated arginine deiminase (ADI-SS PEG20,000 mw) inhibits human melanomas and hepatocellular carcinomas in vitro and in vivo. Cancer Res. 2002;62(19):5443\u201350.","journal-title":"Cancer Res"},{"issue":"26","key":"480_CR14","doi-asserted-by":"publisher","first-page":"4060","DOI":"10.1182\/blood-2014-10-608133","volume":"125","author":"F Miraki-Moud","year":"2015","unstructured":"Miraki-Moud F, Ghazaly E, Ariza-McNaughton L, Hodby KA, Clear A, Anjos-Afonso F, et al. Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo. Blood. 2015;125(26):4060\u20138.","journal-title":"Blood"},{"issue":"12","key":"480_CR15","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1038\/s41419-018-1195-4","volume":"9","author":"JM Przystal","year":"2018","unstructured":"Przystal JM, Hajji N, Khozoie C, Renziehausen A, Zeng Q, Abaitua F, et al. Efficacy of arginine depletion by ADI-PEG20 in an intracranial model of GBM. Cell Death Dis. 2018;9(12):1192.","journal-title":"Cell Death Dis"},{"issue":"1","key":"480_CR16","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1001\/jamaoncol.2016.3049","volume":"3","author":"PW Szlosarek","year":"2017","unstructured":"Szlosarek PW, Steele JP, Nolan L, Gilligan D, Taylor P, Spicer J, et al. Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial. JAMA Oncol. 2017;3(1):58\u201366.","journal-title":"JAMA Oncol"},{"issue":"16","key":"480_CR17","doi-asserted-by":"publisher","first-page":"1778","DOI":"10.1200\/JCO.2016.71.3230","volume":"35","author":"E Beddowes","year":"2017","unstructured":"Beddowes E, Spicer J, Chan PY, Khadeir R, Corbacho JG, Repana D, et al. Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers. J Clin Oncol. 2017;35(16):1778\u201385.","journal-title":"J Clin Oncol"},{"issue":"7","key":"480_CR18","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1517\/13543784.15.7.815","volume":"15","author":"L Feun","year":"2006","unstructured":"Feun L, Savaraj N. Pegylated arginine deiminase: a novel anticancer enzyme agent. Expert Opin Investig Drugs. 2006;15(7):815\u201322.","journal-title":"Expert Opin Investig Drugs"},{"issue":"6","key":"480_CR19","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.1016\/j.celrep.2016.06.097","volume":"16","author":"M Locke","year":"2016","unstructured":"Locke M, Ghazaly E, Freitas MO, Mitsinga M, Lattanzio L, Lo Nigro C, et al. Inhibition of the polyamine synthesis pathway is synthetically lethal with loss of Argininosuccinate synthase 1. Cell Rep. 2016;16(6):1604\u201313.","journal-title":"Cell Rep"},{"issue":"12","key":"480_CR20","doi-asserted-by":"publisher","first-page":"3223","DOI":"10.1158\/1535-7163.MCT-09-0794","volume":"8","author":"WB Tsai","year":"2009","unstructured":"Tsai WB, Aiba I, Lee SY, Feun L, Savaraj N, Kuo MT. Resistance to arginine deiminase treatment in melanoma cells is associated with induced argininosuccinate synthetase expression involving c-Myc\/HIF-1alpha\/Sp4. Mol Cancer Ther. 2009;8(12):3223\u201333.","journal-title":"Mol Cancer Ther"},{"issue":"4","key":"480_CR21","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1165\/rcmb.2011-0195OC","volume":"46","author":"S Battisti","year":"2012","unstructured":"Battisti S, Valente D, Albonici L, Bei R, Modesti A, Palumbo C. Nutritional stress and arginine auxotrophy confer high sensitivity to chloroquine toxicity in mesothelioma cells. Am J Respir Cell Mol Biol. 2012;46(4):498\u2013506.","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"4","key":"480_CR22","volume":"1","author":"PW Szlosarek","year":"2020","unstructured":"Szlosarek PW, Phillips MM, Pavlyk I, Steele J, Shamash J, Spicer J, et al. Expansion phase 1 study of Pegargiminase plus Pemetrexed and cisplatin in patients with Argininosuccinate Synthetase 1-deficient mesothelioma: safety, efficacy, and resistance mechanisms. JTO Clin Res Rep. 2020;1(4): 100093.","journal-title":"JTO Clin Res Rep"},{"issue":"22","key":"480_CR23","doi-asserted-by":"publisher","first-page":"5234","DOI":"10.1002\/cncr.26143","volume":"117","author":"BM Burt","year":"2011","unstructured":"Burt BM, Rodig SJ, Tilleman TR, Elbardissi AW, Bueno R, Sugarbaker DJ. Circulating and tumor-infiltrating myeloid cells predict survival in human pleural mesothelioma. Cancer. 2011;117(22):5234\u201344.","journal-title":"Cancer"},{"issue":"1","key":"480_CR24","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.semcancer.2011.12.005","volume":"22","author":"FR Balkwill","year":"2012","unstructured":"Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol. 2012;22(1):33\u201340.","journal-title":"Semin Cancer Biol"},{"key":"480_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2202\/1544-6115.1027","volume":"3","author":"GK Smyth","year":"2004","unstructured":"Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:1\u201325.","journal-title":"Stat Appl Genet Mol Biol"},{"issue":"13","key":"480_CR26","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.1016\/j.jchromb.2008.12.001","volume":"877","author":"R Pandher","year":"2009","unstructured":"Pandher R, Ducruix C, Eccles SA, Raynaud FI. Cross-platform Q-TOF validation of global exo-metabolomic analysis: application to human glioblastoma cells treated with the standard PI 3-Kinase inhibitor LY294002. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877(13):1352\u20138.","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"issue":"1\u20132","key":"480_CR27","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/0022-1759(94)90012-4","volume":"174","author":"N Van Rooijen","year":"1994","unstructured":"Van Rooijen N, Sanders A. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods. 1994;174(1\u20132):83\u201393.","journal-title":"J Immunol Methods"},{"issue":"4","key":"480_CR28","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1158\/1535-7163.MCT-07-0579","volume":"7","author":"NR Miselis","year":"2008","unstructured":"Miselis NR, Wu ZJ, Van Rooijen N, Kane AB. Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma. Mol Cancer Ther. 2008;7(4):788\u201399.","journal-title":"Mol Cancer Ther"},{"issue":"5","key":"480_CR29","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","volume":"144","author":"D Hanahan","year":"2011","unstructured":"Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646\u201374.","journal-title":"Cell"},{"issue":"1","key":"480_CR30","first-page":"216","volume":"1846","author":"P Icard","year":"2014","unstructured":"Icard P, Kafara P, Steyaert JM, Schwartz L, Lincet H. The metabolic cooperation between cells in solid cancer tumors. Biochim Biophys Acta. 2014;1846(1):216\u201325.","journal-title":"Biochim Biophys Acta"},{"issue":"4","key":"480_CR31","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1158\/1078-0432.CCR-14-2198","volume":"21","author":"IL Romero","year":"2015","unstructured":"Romero IL, Mukherjee A, Kenny HA, Litchfield LM, Lengyel E. Molecular pathways: trafficking of metabolic resources in the tumor microenvironment. Clin Cancer Res. 2015;21(4):680\u20136.","journal-title":"Clin Cancer Res"},{"issue":"11","key":"480_CR32","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1016\/j.tcb.2017.06.003","volume":"27","author":"CA Lyssiotis","year":"2017","unstructured":"Lyssiotis CA, Kimmelman AC. Metabolic interactions in the Tumor microenvironment. Trends Cell Biol. 2017;27(11):863\u201375.","journal-title":"Trends Cell Biol"},{"issue":"1","key":"480_CR33","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1158\/2159-8274.CD-10-0028","volume":"1","author":"DG DeNardo","year":"2011","unstructured":"DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011;1(1):54\u201367.","journal-title":"Cancer Discov"},{"issue":"9","key":"480_CR34","doi-asserted-by":"publisher","first-page":"2782","DOI":"10.1158\/0008-5472.CAN-12-3981","volume":"73","author":"J Xu","year":"2013","unstructured":"Xu J, Escamilla J, Mok S, David J, Priceman S, West B, et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 2013;73(9):2782\u201394.","journal-title":"Cancer Res"},{"issue":"29","key":"480_CR35","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1038\/onc.2013.357","volume":"33","author":"N Weizman","year":"2014","unstructured":"Weizman N, Krelin Y, Shabtay-Orbach A, Amit M, Binenbaum Y, Wong RJ, et al. Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene. 2014;33(29):3812\u20139.","journal-title":"Oncogene"},{"issue":"7","key":"480_CR36","doi-asserted-by":"publisher","first-page":"1652","DOI":"10.1158\/1078-0432.CCR-14-1554","volume":"21","author":"T Wang","year":"2015","unstructured":"Wang T, Xiao M, Ge Y, Krepler C, Belser E, Lopez-Coral A, et al. BRAF inhibition stimulates melanoma-associated macrophages to drive tumor growth. Clin Cancer Res. 2015;21(7):1652\u201364.","journal-title":"Clin Cancer Res"},{"issue":"4","key":"480_CR37","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1016\/j.it.2019.02.003","volume":"40","author":"P Pathria","year":"2019","unstructured":"Pathria P, Louis TL, Varner JA. Targeting tumor-associated macrophages in cancer. Trends Immunol. 2019;40(4):310\u201327.","journal-title":"Trends Immunol"},{"issue":"1","key":"480_CR38","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.immuni.2014.06.010","volume":"41","author":"R Noy","year":"2014","unstructured":"Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49\u201361.","journal-title":"Immunity"},{"issue":"2","key":"480_CR39","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/0014-4827(84)90580-9","volume":"150","author":"JS Davidson","year":"1984","unstructured":"Davidson JS, Baumgarten IM, Harley EH. Metabolic cooperation between argininosuccinate synthetase and argininosuccinate lyase deficient human fibroblasts. Exp Cell Res. 1984;150(2):367\u201378.","journal-title":"Exp Cell Res"},{"issue":"1","key":"480_CR40","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1002\/ijc.22666","volume":"121","author":"PW Szlosarek","year":"2007","unstructured":"Szlosarek PW, Grimshaw MJ, Wilbanks GD, Hagemann T, Wilson JL, Burke F, et al. Aberrant regulation of argininosuccinate synthetase by TNF-alpha in human epithelial ovarian cancer. Int J Cancer. 2007;121(1):6\u201311.","journal-title":"Int J Cancer"},{"issue":"5","key":"480_CR41","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/j.biochi.2005.01.009","volume":"87","author":"C Brasse-Lagnel","year":"2005","unstructured":"Brasse-Lagnel C, Lavoinne A, Fairand A, Vavasseur K, Husson A. IL-1beta stimulates argininosuccinate synthetase gene expression through NF-kappaB in Caco-2 cells. Biochimie. 2005;87(5):403\u20139.","journal-title":"Biochimie"},{"issue":"4","key":"480_CR42","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.2353\/ajpath.2006.040748","volume":"168","author":"WA Boisvert","year":"2006","unstructured":"Boisvert WA, Rose DM, Johnson KA, Fuentes ME, Lira SA, Curtiss LK, et al. Up-regulated expression of the CXCR2 ligand KC\/GRO-alpha in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression. Am J Pathol. 2006;168(4):1385\u201395.","journal-title":"Am J Pathol"},{"issue":"2","key":"480_CR43","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1161\/01.CIR.102.2.185","volume":"102","author":"J Waltenberger","year":"2000","unstructured":"Waltenberger J, Lange J, Kranz A. Vascular endothelial growth factor-A-induced chemotaxis of monocytes is attenuated in patients with diabetes mellitus: a potential predictor for the individual capacity to develop collaterals. Circulation. 2000;102(2):185\u201390.","journal-title":"Circulation"},{"issue":"7203","key":"480_CR44","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1038\/nature07203","volume":"454","author":"K Zhang","year":"2008","unstructured":"Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008;454(7203):455\u201362.","journal-title":"Nature"},{"issue":"5","key":"480_CR45","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1016\/j.ccr.2014.03.015","volume":"25","author":"HJ Clarke","year":"2014","unstructured":"Clarke HJ, Chambers JE, Liniker E, Marciniak SJ. Endoplasmic reticulum stress in malignancy. Cancer Cell. 2014;25(5):563\u201373.","journal-title":"Cancer Cell"},{"issue":"6","key":"480_CR46","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1016\/j.ccr.2012.10.023","volume":"22","author":"A Britschgi","year":"2012","unstructured":"Britschgi A, Andraos R, Brinkhaus H, Klebba I, Romanet V, Muller U, et al. JAK2\/STAT5 inhibition circumvents resistance to PI3K\/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell. 2012;22(6):796\u2013811.","journal-title":"Cancer Cell"},{"issue":"22","key":"480_CR47","doi-asserted-by":"publisher","first-page":"5697","DOI":"10.1158\/1078-0432.CCR-13-3203","volume":"20","author":"MF Sanmamed","year":"2014","unstructured":"Sanmamed MF, Carranza-Rua O, Alfaro C, Onate C, Martin-Algarra S, Perez G, et al. Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins. Clin Cancer Res. 2014;20(22):5697\u2013707.","journal-title":"Clin Cancer Res"},{"key":"480_CR48","doi-asserted-by":"publisher","first-page":"4900","DOI":"10.1038\/ncomms5900","volume":"5","author":"NP Shanware","year":"2014","unstructured":"Shanware NP, Bray K, Eng CH, Wang F, Follettie M, Myers J, et al. Glutamine deprivation stimulates mTOR-JNK-dependent chemokine secretion. Nat Commun. 2014;5:4900.","journal-title":"Nat Commun"},{"issue":"5","key":"480_CR49","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.3390\/molecules28052150","volume":"28","author":"GC Field","year":"2023","unstructured":"Field GC, Pavlyk I, Szlosarek PW. Bench-to-bedside studies of arginine deprivation in cancer. Molecules. 2023;28(5):2150.","journal-title":"Molecules"},{"key":"480_CR50","doi-asserted-by":"publisher","first-page":"126","DOI":"10.3389\/fonc.2020.00126","volume":"10","author":"AK Nowak","year":"2020","unstructured":"Nowak AK, Brosseau S, Cook A, Zalcman G. Antiangiogeneic strategies in mesothelioma. Front Oncol. 2020;10:126.","journal-title":"Front Oncol"},{"issue":"6","key":"480_CR51","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1016\/j.ccr.2014.05.016","volume":"25","author":"CH Ries","year":"2014","unstructured":"Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. 2014;25(6):846\u201359.","journal-title":"Cancer Cell"},{"issue":"5","key":"480_CR52","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1158\/1535-7163.MCT-12-0529","volume":"12","author":"B Sharma","year":"2013","unstructured":"Sharma B, Nawandar DM, Nannuru KC, Varney ML, Singh RK. Targeting CXCR2 enhances chemotherapeutic response, inhibits mammary tumor growth, angiogenesis, and lung metastasis. Mol Cancer Ther. 2013;12(5):799\u2013808.","journal-title":"Mol Cancer Ther"},{"key":"480_CR53","doi-asserted-by":"crossref","unstructured":"Chu CY, Lee YC, Hsieh CH, Yeh CT, Chao TY, Chen PH, et al. (2021) Genome-wide CRISPR\/Cas9 knockout screening uncovers a novel inflammatory pathway critical for resistance to arginine-deprivation therapy. Theranostics 11:3624-3641","DOI":"10.7150\/thno.51795"}],"updated-by":[{"DOI":"10.1007\/s43440-023-00487-z","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T00:00:00Z","timestamp":1684281600000}}],"container-title":["Pharmacological Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43440-023-00480-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s43440-023-00480-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43440-023-00480-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,10]],"date-time":"2023-12-10T04:07:34Z","timestamp":1702181254000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s43440-023-00480-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,3]]},"references-count":53,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2023,6]]}},"alternative-id":["480"],"URL":"https:\/\/doi.org\/10.1007\/s43440-023-00480-6","relation":{"correction":[{"id-type":"doi","id":"10.1007\/s43440-023-00487-z","asserted-by":"object"}]},"ISSN":["1734-1140","2299-5684"],"issn-type":[{"value":"1734-1140","type":"print"},{"value":"2299-5684","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,3]]},"assertion":[{"value":"23 January 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 March 2023","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 March 2023","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 April 2023","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 May 2023","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1007\/s43440-023-00487-z","URL":"https:\/\/doi.org\/10.1007\/s43440-023-00487-z","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"PWS has received funding research support from Polaris Pharmaceuticals Inc.; JB is an employee of Polaris Pharmaceuticals Inc.; and the other authors declare no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}