{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:01:13Z","timestamp":1784818873873,"version":"3.55.0"},"reference-count":66,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T00:00:00Z","timestamp":1675123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013297","name":"Eurostars","doi-asserted-by":"publisher","award":["E! 113736"],"award-info":[{"award-number":["E! 113736"]}],"id":[{"id":"10.13039\/100013297","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013297","name":"Eurostars","doi-asserted-by":"publisher","award":["2017-02"],"award-info":[{"award-number":["2017-02"]}],"id":[{"id":"10.13039\/100013297","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Stichting Ruby and Rose","award":["E! 113736"],"award-info":[{"award-number":["E! 113736"]}]},{"name":"Stichting Ruby and Rose","award":["2017-02"],"award-info":[{"award-number":["2017-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The molecular mechanisms contributing to immune suppression in ovarian cancer are not well understood, hampering the successful application of immunotherapy. Amino acid-metabolizing enzymes are known to contribute to the immune-hostile environment of various tumors through depletion of amino acids and production of immunosuppressive metabolites. We aimed to collectively evaluate the activity of these enzymes in high-grade serous ovarian cancer patients by performing targeted metabolomics on plasma and ascites samples. Whereas no indication was found for enhanced l-arginine or l-glutamine metabolism by immunosuppressive enzymes in ovarian cancer patients, metabolism of l-tryptophan by indoleamine 2,3-dioxygenase 1 (IDO1) was significantly elevated compared to healthy controls. Moreover, high levels of l-phenylalanine- and l-tyrosine-derived metabolites associated with interleukin 4 induced 1 (IL4I1) activity were found in ovarian cancer ascites samples. While l-tryptophan is a major substrate of both IDO1 and IL4I1, only its enhanced conversion into l-kynurenine by IDO1 could be detected, despite the observed activity of IL4I1 on its other substrates. In ascites of ovarian cancer patients, metabolite levels were higher compared to those in plasma, demonstrating the value of utilizing this fluid for biomarker identification. Finally, elevated metabolism of l-phenylalanine and l-tyrosine by IL4I1 correlated with disease stage, pointing towards a potential role for IL4I1 in ovarian cancer progression.<\/jats:p>","DOI":"10.3390\/cancers15030893","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T05:33:53Z","timestamp":1675229633000},"page":"893","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Amino Acid-Metabolizing Enzymes in Advanced High-Grade Serous Ovarian Cancer Patients: Value of Ascites as Biomarker Source and Role for IL4I1 and IDO1"],"prefix":"10.3390","volume":"15","author":[{"given":"Yvonne","family":"Grobben","sequence":"first","affiliation":[{"name":"Oncolines B.V., 5349 AB Oss, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith E.","family":"den Ouden","sequence":"additional","affiliation":[{"name":"Radboud Institute for Health Sciences, Radboud University Medical Center, Obstetrics and Gynecology, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Aguado","sequence":"additional","affiliation":[{"name":"Laboratory of Oncology, Pangaea Oncology, Dexeus University Hospital, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"van Altena","sequence":"additional","affiliation":[{"name":"Radboud Institute for Health Sciences, Radboud University Medical Center, Obstetrics and Gynecology, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9819-383X","authenticated-orcid":false,"given":"Aletta D.","family":"Kraneveld","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido J. R.","family":"Zaman","sequence":"additional","affiliation":[{"name":"Oncolines B.V., 5349 AB Oss, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer Statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA. Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"284","DOI":"10.3322\/caac.21456","article-title":"Ovarian Cancer Statistics, 2018","volume":"68","author":"Torre","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","unstructured":"American Cancer Society (2022). Cancer Facts & Figures 2022, American Cancer Society."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1097\/AOG.0000000000004173","article-title":"Updates and New Options in Advanced Epithelial Ovarian Cancer Treatment","volume":"137","author":"Kurnit","year":"2021","journal-title":"Obstet. Gynecol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"McMullen, M., Karakasis, K., Madariaga, A., and Oza, A.M. (2020). Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer. Cancers, 12.","DOI":"10.3390\/cancers12061607"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.1038\/s41467-020-17670-y","article-title":"A Decade of Immune-Checkpoint Inhibitors in Cancer Therapy","volume":"11","author":"Robert","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev-pathol-042020-042741","article-title":"Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance","volume":"16","author":"Bagchi","year":"2021","journal-title":"Annu. Rev. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s40661-016-0033-6","article-title":"The Role of Immune Checkpoint Inhibition in the Treatment of Ovarian Cancer","volume":"3","author":"Gaillard","year":"2016","journal-title":"Gynecol. Oncol. Res. Pract."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Rodriguez, G.M., Galpin, K.J.C., McCloskey, C.W., and Vanderhyden, B.C. (2018). The Tumor Microenvironment of Epithelial Ovarian Cancer and Its Influence on Response to Immunotherapy. Cancers, 10.","DOI":"10.3390\/cancers10080242"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"589508","DOI":"10.3389\/fonc.2020.589508","article-title":"Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies","volume":"10","author":"Wang","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"938","DOI":"10.3389\/fimmu.2020.00938","article-title":"Myeloid Cell-Derived Arginase in Cancer Immune Response","volume":"11","author":"Grzywa","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.trsl.2019.03.003","article-title":"Immunomodulatory Roles of Nitric Oxide in Cancer: Tumor Microenvironment Says \u201cNO\u201d to Antitumor Immune Response","volume":"210","author":"Aranda","year":"2019","journal-title":"Transl. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41416-019-0664-6","article-title":"The Therapeutic Potential of Targeting Tryptophan Catabolism in Cancer","volume":"122","author":"Opitz","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.immuni.2017.12.012","article-title":"Regulation of the Immune Response by the Aryl Hydrocarbon Receptor","volume":"48","author":"Quintana","year":"2018","journal-title":"Immunity"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature10491","article-title":"An Endogenous Tumour-Promoting Ligand of the Human Aryl Hydrocarbon Receptor","volume":"478","author":"Opitz","year":"2011","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1158\/2326-6066.CIR-19-0040","article-title":"Tryptophan 2,3-Dioxygenase Expression Identified in Human Hepatocellular Carcinoma Cells and in Intratumoral Pericytes of Most Cancers","volume":"8","author":"Hoffmann","year":"2020","journal-title":"Cancer Immunol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1038\/leu.2008.380","article-title":"The Novel Immunosuppressive Enzyme IL4I1 Is Expressed by Neoplastic Cells of Several B-Cell Lymphomas and by Tumor-Associated Macrophages","volume":"23","author":"Baia","year":"2009","journal-title":"Leukemia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1016\/j.cell.2020.07.038","article-title":"IL4I1 Is a Metabolic Immune Checkpoint That Activates the AHR and Promotes Tumor Progression","volume":"182","author":"Sadik","year":"2020","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1182\/blood-2006-07-036210","article-title":"Human IL4I1 Is a Secreted L-Phenylalanine Oxidase Expressed by Mature Dendritic Cells That Inhibits T-Lymphocyte Proliferation","volume":"110","author":"Boulland","year":"2007","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1038\/nm934","article-title":"Evidence for a Tumoral Immune Resistance Mechanism Based on Tryptophan Degradation by Indoleamine 2,3-Dioxygenase","volume":"9","author":"Uyttenhove","year":"2003","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s40425-017-0308-4","article-title":"Inhibition of Arginase by CB-1158 Blocks Myeloid Cell-Mediated Immune Suppression in the Tumor Microenvironment","volume":"5","author":"Steggerda","year":"2017","journal-title":"J. Immunother. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1007\/s00595-002-2563-2","article-title":"Elevated Serum Arginase Activity Levels in Patients with Breast Cancer","volume":"33","author":"Polat","year":"2003","journal-title":"Surg. Today"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1178646919868978","DOI":"10.1177\/1178646919868978","article-title":"The Plasma [Kynurenine]\/[Tryptophan] Ratio and Indoleamine 2,3-Dioxygenase: Time for Appraisal","volume":"12","author":"Badawy","year":"2019","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.4155\/bio.13.74","article-title":"A Simple LC-MS\/MS Method for Determination of Kynurenine and Tryptophan Concentrations in Human Plasma from HIV-Infected Patients","volume":"5","author":"Huang","year":"2013","journal-title":"Bioanalysis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.4155\/bio.12.200","article-title":"Surrogate Matrix and Surrogate Analyte Approaches for Definitive Quantitation of Endogenous Biomolecules","volume":"4","author":"Jones","year":"2012","journal-title":"Bioanalysis"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Rickard, B.P., Conrad, C., Sorrin, A.J., Ruhi, M.K., Reader, J.C., Huang, S.A., Franco, W., Scarcelli, G., Polacheck, W.J., and Roque, D.M. (2021). Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response. Cancers, 13.","DOI":"10.3390\/cancers13174318"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sardar, P., and Kempken, F. (2018). Characterization of Indole-3-Pyruvic Acid Pathway-Mediated Biosynthesis of Auxin in Neurospora Crassa. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0192293"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1124\/mol.64.3.550","article-title":"Aspartate Aminotransferase Generates Proagonists of the Aryl Hydrocarbon Receptor","volume":"64","author":"Bittinger","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4561","DOI":"10.4049\/jimmunol.173.7.4561","article-title":"IL-4-Induced Gene-1 Is a Leukocyte L-Amino Acid Oxidase with an Unusual Acidic PH Preference and Lysosomal Localization","volume":"173","author":"Mason","year":"2004","journal-title":"J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e64806","DOI":"10.7554\/eLife.64806","article-title":"Anti-Ferroptotic Mechanism of IL4i1-Mediated Amino Acid Metabolism","volume":"10","author":"Zeitler","year":"2021","journal-title":"eLife"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1183\/16000617.0019-2016","article-title":"Malignant Pleural Effusion: From Bench to Bedside","volume":"25","author":"Psallidas","year":"2016","journal-title":"Eur. Respir. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6030","DOI":"10.1158\/1078-0432.CCR-04-2671","article-title":"Indoleamine 2,3-Dioxygenase Serves as a Marker of Poor Prognosis in Gene Expression Profiles of Serous Ovarian Cancer Cells","volume":"11","author":"Okamoto","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_33","first-page":"1333","article-title":"Increased Synthesis of Indoleamine-2,3-Dioxygenase Protein Is Positively Associated with Impaired Survival in Patients with Serous-Type, but Not with Other Types of, Ovarian Cancer","volume":"17","author":"Takao","year":"2007","journal-title":"Oncol. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ygyno.2009.07.015","article-title":"Role of the Immunosuppressive Enzyme Indoleamine 2,3-Dioxygenase in the Progression of Ovarian Carcinoma","volume":"115","author":"Inaba","year":"2009","journal-title":"Gynecol. Oncol."},{"key":"ref_35","first-page":"1320","article-title":"Serum Tryptophan and Kynurenine Concentrations as Parameters for Indoleamine 2,3-Dioxygenase Activity in Patients with Endometrial, Ovarian, and Vulvar Cancer","volume":"21","author":"Nijman","year":"2011","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.imbio.2010.07.010","article-title":"Enhanced Tryptophan Degradation in Patients with Ovarian Carcinoma Correlates with Several Serum Soluble Immune Activation Markers","volume":"216","author":"Neurauter","year":"2011","journal-title":"Immunobiology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.ygyno.2018.02.020","article-title":"Immunobiochemical Pathways of Neopterin Formation and Tryptophan Breakdown via Indoleamine 2,3-Dioxygenase Correlate with Circulating Tumor Cells in Ovarian Cancer Patients- A Study of the OVCAD Consortium","volume":"149","author":"Gostner","year":"2018","journal-title":"Gynecol. Oncol."},{"key":"ref_38","first-page":"1","article-title":"Tryptophan Catabolism in Epithelial Ovarian Carcinoma","volume":"14","author":"Smith","year":"2019","journal-title":"Trends Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"609490","DOI":"10.3389\/fimmu.2020.609490","article-title":"Targeting Indoleamine 2,3-Dioxygenase in Cancer Models Using the Novel Small Molecule Inhibitor NTRC 3883-0","volume":"11","author":"Grobben","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1177\/1087057114536616","article-title":"High-Throughput Fluorescence-Based Screening Assays for Tryptophan-Catabolizing Enzymes","volume":"19","author":"Seegers","year":"2014","journal-title":"J. Biomol. Screen."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/S1470-2045(19)30274-8","article-title":"Epacadostat plus Pembrolizumab versus Placebo plus Pembrolizumab in Patients with Unresectable or Metastatic Melanoma (ECHO-301\/KEYNOTE-252): A Phase 3, Randomised, Double-Blind Study","volume":"20","author":"Long","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1146\/annurev-cancerbio-030419-033635","article-title":"Is There a Clinical Future for IDO1 Inhibitors after the Failure of Epacadostat in Melanoma?","volume":"4","author":"Baurain","year":"2020","journal-title":"Annu. Rev. Cancer Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s00281-018-0702-0","article-title":"Inhibiting IDO Pathways to Treat Cancer: Lessons from the ECHO-301 Trial and Beyond","volume":"41","author":"Muller","year":"2019","journal-title":"Semin. Immunopathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"11508","DOI":"10.1021\/bi980087p","article-title":"Activation of the Ah Receptor by Tryptophan and Tryptophan Metabolites","volume":"37","author":"Rogers","year":"1998","journal-title":"Biochemistry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1093\/toxsci\/kfq024","article-title":"Kynurenic Acid Is a Potent Endogenous Aryl Hydrocarbon Receptor Ligand That Synergistically Induces Interleukin-6 in the Presence of Inflammatory Signaling","volume":"115","author":"DiNatale","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ehrlich, A.M., Pacheco, A.R., Henrick, B.M., Taft, D., Xu, G., Huda, M.N., Mishchuk, D., Goodson, M.L., Slupsky, C., and Barile, D. (2020). Indole-3-Lactic Acid Associated with Bifidobacterium-Dominated Microbiota Significantly Decreases Inflammation in Intestinal Epithelial Cells. BMC Microbiol., 20.","DOI":"10.1186\/s12866-020-02023-y"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1924500","DOI":"10.1080\/2162402X.2021.1924500","article-title":"What Role for AHR Activation in IL4I1-Mediated Immunosuppression ?","volume":"10","author":"Castellano","year":"2021","journal-title":"Oncoimmunology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"109091","DOI":"10.1016\/j.intimp.2022.109091","article-title":"Pan-Cancer Analysis Combined with Experimental Validation Revealed IL4I1 as an Immunological and Prognostic Biomarker","volume":"111","author":"Rao","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1186\/s12967-021-03123-7","article-title":"Single-Cell Analysis Revealed That IL4I1 Promoted Ovarian Cancer Progression","volume":"19","author":"Zhao","year":"2021","journal-title":"J. Transl. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1002\/1878-0261.12574","article-title":"Prospective Detection of Mutations in Cerebrospinal Fluid, Pleural Effusion, and Ascites of Advanced Cancer Patients to Guide Treatment Decisions","volume":"13","author":"Villatoro","year":"2019","journal-title":"Mol. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1074\/mcp.M800313-MCP200","article-title":"Mining the Ovarian Cancer Ascites Proteome for Potential Ovarian Cancer Biomarkers","volume":"8","author":"Kuk","year":"2009","journal-title":"Mol. Cell. Proteom."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Fong, M.Y., McDunn, J., and Kakar, S.S. (2011). Identification of Metabolites in the Normal Ovary and Their Transformation in Primary and Metastatic Ovarian Cancer. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019963"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.molimm.2008.08.266","article-title":"Murine Ovarian Cancer Vascular Leukocytes Require Arginase-1 Activity for T Cell Suppression","volume":"46","author":"Bak","year":"2008","journal-title":"Mol. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3000","DOI":"10.1038\/s41467-019-10979-3","article-title":"Small Extracellular Vesicles Containing Arginase-1 Suppress T-Cell Responses and Promote Tumor Growth in Ovarian Carcinoma","volume":"10","author":"Sosnowska","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/nrc1910","article-title":"The Role of Nitric Oxide in Tumour Progression","volume":"6","author":"Fukumura","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"186584","DOI":"10.1155\/2008\/186584","article-title":"Production of Nitric Oxide and Expression of Inducible Nitric Oxide Synthase in Ovarian Cystic Tumors","volume":"2008","author":"Nomelini","year":"2008","journal-title":"Mediators Inflamm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4514","DOI":"10.1158\/0008-5472.CAN-19-3971","article-title":"Inhibition of the MYC-Regulated Glutaminase Metabolic Axis Is an Effective Synthetic Lethal Approach for Treating Chemoresistant Ovarian Cancers","volume":"80","author":"Shen","year":"2020","journal-title":"Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Plewa, S., Hora\u0142a, A., Derezi\u0144ski, P., Klupczynska, A., Nowak-Markwitz, E., Matysiak, J., and Kokot, Z.J. (2017). Usefulness of Amino Acid Profiling in Ovarian Cancer Screening with Special Emphasis on Their Role in Cancerogenesis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122727"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.ygyno.2021.08.001","article-title":"Platinum Resistance in Gynecologic Malignancies: Response, Disease Free and Overall Survival Are Predicted by Biochemical Signature: A Metabolomic Analysis","volume":"163","author":"Silva","year":"2021","journal-title":"Gynecol. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/ijc.22666","article-title":"Aberrant Regulation of Argininosuccinate Synthetase by TNF-Alpha in Human Epithelial Ovarian Cancer","volume":"121","author":"Szlosarek","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/cjp2.4","article-title":"Differential Expression of Argininosuccinate Synthetase in Serous and Non-Serous Ovarian Carcinomas","volume":"1","author":"Cheon","year":"2015","journal-title":"J. Pathol. Clin. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.3892\/or.2015.4280","article-title":"Argininosuccinate Lyase Is a Potential Therapeutic Target in Breast Cancer","volume":"34","author":"Huang","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.gendis.2018.11.003","article-title":"Down-Regulation of Argininosuccinate Lyase Induces Hepatoma Cell Apoptosis through Activating Bax Signaling Pathway","volume":"6","author":"Gong","year":"2019","journal-title":"Genes Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"BSR20203827","DOI":"10.1042\/BSR20203827","article-title":"Effects of Storage Time and Temperature on Highly Multiparametric Flow Analysis of Peripheral Blood Samples; Implications for Clinical Trial Samples","volume":"41","author":"Jerram","year":"2021","journal-title":"Biosci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Davis, J.S., Darcy, C.J., Piera, K., McNeil, Y.R., Woodberry, T., and Anstey, N.M. (2009). Ex-Vivo Changes in Amino Acid Concentrations from Blood Stored at Room Temperature or on Ice: Implications for Arginine and Taurine Measurements. BMC Clin. Pathol., 9.","DOI":"10.1186\/1472-6890-9-10"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Stevens, V.L., Hoover, E., Wang, Y., and Zanetti, K.A. (2019). Pre-Analytical Factors That Affect Metabolite Stability in Human Urine, Plasma, and Serum: A Review. Metabolites, 9.","DOI":"10.3390\/metabo9080156"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/3\/893\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:19:57Z","timestamp":1760120397000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/3\/893"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,31]]},"references-count":66,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["cancers15030893"],"URL":"https:\/\/doi.org\/10.3390\/cancers15030893","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,31]]}}}