BACKGROUND: Pancreatic cancer is the most common pancreatic solid malignancy with an aggressive clinical course and low survival rate. There are a limited number of reliable prognostic biomarkers and a need to understand the pathogenesis of pancreatic tumors; neuroendocrine (PNET) and pancreatic ductal adenocarcinomas (PDAC) encouraged us to analyze the serum metabolome of pancreatic tumors and disturbances in the metabolism of PDAC and PNET. METHODS: Using the AbsoluteIDQ® p180 kit (Biocrates Life Sciences AG, Innsbruck, Austria) with liquid chromatography-mass spectrometry (LC-MS), we identified changes in metabolite profiles and disrupted metabolic pathways serum of NET and PDAC patients. RESULTS: The concentration of six metabolites showed statistically significant differences between the control group and PDAC patients (p.adj < 0.05). Glutamine (Gln), acetylcarnitine (C2), and citrulline (Cit) presented a lower concentration in the serum of PDAC patients, while phosphatidylcholine aa C32:0 (PC aa C32:0), sphingomyelin C26:1 (SM C26:1), and glutamic acid (Glu) achieved higher concentrations compared to serum samples from healthy individuals. Five of the tested metabolites: C2 (FC = 8.67), and serotonin (FC = 2.68) reached higher concentration values in the PNET serum samples compared to PDAC, while phosphatidylcholine aa C34:1 (PC aa C34:1) (FC = -1.46 (0.68)) had a higher concentration in the PDAC samples. The area under the curves (AUC) of the receiver operating characteristic (ROC) curves presented diagnostic power to discriminate pancreatic tumor patients, which were highest for acylcarnitines: C2 with AUC = 0.93, serotonin with AUC = 0.85, and PC aa C34:1 with AUC = 0.86. CONCLUSIONS: The observations presented provide better insight into the metabolism of pancreatic tumors, and improve the diagnosis and classification of tumors. Serum-circulating metabolites can be easily monitored without invasive procedures and show the present clinical patients' condition, helping with pharmacological treatment or dietary strategies.

Department of Endocrinology and Neuroendocrine Tumours Department of Pathophysiology and Endocrinology Medical University of Silesia 40 752 Katowice Poland

Department of Gastroenterology Pomeranian Medical University in Szczecin 70 204 Szczecin Poland

Department of General Minimally Invasive and Gastroenterological Surgery Pomeranian Medical University in Szczecin 70 204 Szczecin Poland

Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age Pediatric Hospital of Medical University of Warsaw 02 091 Warsaw Poland

Institute of Health Sciences Faculty of Medical and Health Sciences Siedlce University of Natural Sciences and Humanities 08 110 Siedlce Poland

Laboratory of Translational Cancer Genomics Biomedical Center Faculty of Medicine in Pilsen Charles University Alej Svobody 1665 76 32300 Pilsen Czech Republic

Mass Spectrometry Laboratory Institute of Biochemistry and Biophysics Polish Academy of Sciences 02 106 Warsaw Poland

Molecular Biology Laboratory Department of Diagnostic Hematology Institute of Hematology and Transfusion Medicine 02 776 Warsaw Poland

The Department of Gastrointestinal Surgery Medical University of Silesia 40 752 Katowice Poland

Zobrazit více v PubMed

Cao Y., Zhao R., Guo K., Ren S., Zhang Y., Lu Z., Tian L., Li T., Chen X., Wang Z. Potential Metabolite Biomarkers for Early Detection of Stage-I Pancreatic Ductal Adenocarcinoma. Front. Oncol. 2021;11:744667. doi: 10.3389/fonc.2021.744667. PubMed DOI PMC

Maisonneuve P. Epidemiology and Burden of Pancreatic Cancer. Presse Med. 2019;48:e113–e123. doi: 10.1016/j.lpm.2019.02.030. PubMed DOI

Halbrook C.J., Lyssiotis C.A. Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer. Cancer Cell. 2017;31:5–19. doi: 10.1016/j.ccell.2016.12.006. PubMed DOI

McGuigan A., Kelly P., Turkington R.C., Jones C., Coleman H.G., McCain R.S. Pancreatic Cancer: A Review of Clinical Diagnosis, Epidemiology, Treatment and Outcomes. World J. Gastroenterol. 2018;24:4846–4861. doi: 10.3748/wjg.v24.i43.4846. PubMed DOI PMC

Qin C., Yang G., Yang J., Ren B., Wang H., Chen G., Zhao F., You L., Wang W., Zhao Y. Metabolism of Pancreatic Cancer: Paving the Way to Better Anticancer Strategies. Mol. Cancer. 2020;19:50. doi: 10.1186/s12943-020-01169-7. PubMed DOI PMC

Zhang X., Shi X., Lu X., Li Y., Zhan C., Akhtar M.L., Yang L., Bai Y., Zhao J., Wang Y., et al. Novel Metabolomics Serum Biomarkers for Pancreatic Ductal Adenocarcinoma by the Comparison of Pre-, Postoperative and Normal Samples. J. Cancer. 2020;11:4641–4651. doi: 10.7150/jca.41250. PubMed DOI PMC

Mayerle J., Kalthoff H., Reszka R., Kamlage B., Peter E., Schniewind B., González Maldonado S., Pilarsky C., Heidecke C.-D., Schatz P., et al. Metabolic Biomarker Signature to Differentiate Pancreatic Ductal Adenocarcinoma from Chronic Pancreatitis. Gut. 2018;67:128–137. doi: 10.1136/gutjnl-2016-312432. PubMed DOI PMC

Stolzenberg-Solomon R., Derkach A., Moore S., Weinstein S.J., Albanes D., Sampson J. Associations between Metabolites and Pancreatic Cancer Risk in a Large Prospective Epidemiological Study. Gut. 2020;69:2008–2015. doi: 10.1136/gutjnl-2019-319811. PubMed DOI PMC

Vincent A., Herman J., Schulick R., Hruban R.H., Goggins M. Pancreatic Cancer. Lancet. 2011;378:607–620. doi: 10.1016/S0140-6736(10)62307-0. PubMed DOI PMC

Zhou Q., Melton D.A. Pancreas Regeneration. Nature. 2018;557:351–358. doi: 10.1038/s41586-018-0088-0. PubMed DOI PMC

Suzuki T., Otsuka M., Seimiya T., Iwata T., Kishikawa T., Koike K. The Biological Role of Metabolic Reprogramming in Pancreatic Cancer. MedComm. 2020;1:302–310. doi: 10.1002/mco2.37. PubMed DOI PMC

Mpilla G.B., Philip P.A., El-Rayes B., Azmi A.S. Pancreatic Neuroendocrine Tumors: Therapeutic Challenges and Research Limitations. World J. Gastroenterol. 2020;26:4036–4054. doi: 10.3748/wjg.v26.i28.4036. PubMed DOI PMC

Rossi R.E., Ciafardini C., Sciola V., Conte D., Massironi S. Chromogranin A in the Follow-up of Gastroenteropancreatic Neuroendocrine Neoplasms: Is It Really Game Over? A Systematic Review and Meta-Analysis. Pancreas. 2018;47:1249–1255. doi: 10.1097/MPA.0000000000001184. PubMed DOI

Malczewska A., Witkowska M., Wójcik-Giertuga M., Kuśnierz K., Bocian A., Walter A., Rydel M., Robek A., Pierzchała S., Malczewska M., et al. Prospective Evaluation of the NETest as a Liquid Biopsy for Gastroenteropancreatic and Bronchopulmonary Neuroendocrine Tumors: An ENETS Center of Excellence Experience. Neuroendocrinology. 2021;111:304–319. doi: 10.1159/000508106. PubMed DOI

Modlin I.M., Kidd M., Falconi M., Filosso P.L., Frilling A., Malczewska A., Toumpanakis C., Valk G., Pacak K., Bodei L., et al. A Multigenomic Liquid Biopsy Biomarker for Neuroendocrine Tumor Disease Outperforms CgA and Has Surgical and Clinical Utility. Ann. Oncol. 2021;32:1425–1433. doi: 10.1016/j.annonc.2021.08.1746. PubMed DOI PMC

Alexandraki K.I., Spyroglou A., Kykalos S., Daskalakis K., Kyriakopoulos G., Sotiropoulos G.C., Kaltsas G.A., Grossman A.B. Changing Biological Behaviour of NETs during the Evolution of the Disease: Progress on Progression. Endocr. Relat. Cancer. 2021;28:R121–R140. doi: 10.1530/ERC-20-0473. PubMed DOI

Guadagno E., D’Avella E., Cappabianca P., Colao A., Del Basso De Caro M. Ki67 in Endocrine Neoplasms: To Count or Not to Count, This Is the Question! A Systematic Review from the English Language Literature. J. Endocrinol. Investig. 2020;43:1429–1445. doi: 10.1007/s40618-020-01275-9. PubMed DOI

Lea D., Gudlaugsson E.G., Skaland I., Lillesand M., Søreide K., Søreide J.A. Digital Image Analysis of the Proliferation Markers Ki67 and Phosphohistone H3 in Gastroenteropancreatic Neuroendocrine Neoplasms: Accuracy of Grading Compared With Routine Manual Hot Spot Evaluation of the Ki67 Index. Appl. Immunohistochem. Mol. Morphol. 2021;29:499–505. doi: 10.1097/PAI.0000000000000934. PubMed DOI PMC

Dambrova M., Makrecka-Kuka M., Kuka J., Vilskersts R., Nordberg D., Attwood M.M., Smesny S., Sen Z.D., Guo A.C., Oler E., et al. Acylcarnitines: Nomenclature, Biomarkers, Therapeutic Potential, Drug Targets, and Clinical Trials. Pharmacol. Rev. 2022;74:506–551. doi: 10.1124/pharmrev.121.000408. PubMed DOI

Wang Y., Chen Y., Guan L., Zhang H., Huang Y., Johnson C.H., Wu Z., Gonzalez F.J., Yu A., Huang P., et al. Carnitine Palmitoyltransferase 1C Regulates Cancer Cell Senescence through Mitochondria-Associated Metabolic Reprograming. Cell Death Differ. 2018;25:735–748. doi: 10.1038/s41418-017-0013-3. PubMed DOI PMC

Fujiwara N., Nakagawa H., Enooku K., Kudo Y., Hayata Y., Nakatsuka T., Tanaka Y., Tateishi R., Hikiba Y., Misumi K., et al. CPT2 Downregulation Adapts HCC to Lipid-Rich Environment and Promotes Carcinogenesis via Acylcarnitine Accumulation in Obesity. Gut. 2018;67:1493–1504. doi: 10.1136/gutjnl-2017-315193. PubMed DOI PMC

Bruls Y.M., de Ligt M., Lindeboom L., Phielix E., Havekes B., Schaart G., Kornips E., Wildberger J.E., Hesselink M.K., Muoio D., et al. Carnitine Supplementation Improves Metabolic Flexibility and Skeletal Muscle Acetylcarnitine Formation in Volunteers with Impaired Glucose Tolerance: A Randomised Controlled Trial. EBioMedicine. 2019;49:318–330. doi: 10.1016/j.ebiom.2019.10.017. PubMed DOI PMC

Askarpour M., Hadi A., Miraghajani M., Symonds M.E., Sheikhi A., Ghaedi E. Beneficial Effects of L-Carnitine Supplementation for Weight Management in Overweight and Obese Adults: An Updated Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials. Pharmacol. Res. 2020;151:104554. doi: 10.1016/j.phrs.2019.104554. PubMed DOI

Wu C., Zhu M., Lu Z., Zhang Y., Li L., Li N., Yin L., Wang H., Song W., Xu H. L-Carnitine Ameliorates the Muscle Wasting of Cancer Cachexia through the AKT/FOXO3a/MaFbx Axis. Nutr. Metab. 2021;18:98. doi: 10.1186/s12986-021-00623-7. PubMed DOI PMC

Takagi A., Hawke P., Tokuda S., Toda T., Higashizono K., Nagai E., Watanabe M., Nakatani E., Kanemoto H., Oba N. Serum Carnitine as a Biomarker of Sarcopenia and Nutritional Status in Preoperative Gastrointestinal Cancer Patients. J. Cachexia Sarcopenia Muscle. 2022;13:287–295. doi: 10.1002/jcsm.12906. PubMed DOI PMC

Mochamat, Cuhls H., Marinova M., Kaasa S., Stieber C., Conrad R., Radbruch L., Mücke M. A Systematic Review on the Role of Vitamins, Minerals, Proteins, and Other Supplements for the Treatment of Cachexia in Cancer: A European Palliative Care Research Centre Cachexia Project. J. Cachexia Sarcopenia Muscle. 2017;8:25–39. doi: 10.1002/jcsm.12127. PubMed DOI PMC

Mock-Ohnesorge J., Mock A., Hackert T., Fröhling S., Schenz J., Poschet G., Jäger D., Büchler M.W., Uhle F., Weigand M.A. Perioperative Changes in the Plasma Metabolome of Patients Receiving General Anesthesia for Pancreatic Cancer Surgery. Oncotarget. 2021;12:996–1010. doi: 10.18632/oncotarget.27956. PubMed DOI PMC

Li T., Le A. Glutamine Metabolism in Cancer. Adv. Exp. Med. Biol. 2018;1063:13–32. doi: 10.1007/978-3-319-77736-8_2. PubMed DOI

Dunphy M.P.S., Harding J.J., Venneti S., Zhang H., Burnazi E.M., Bromberg J., Omuro A.M., Hsieh J.J., Mellinghoff I.K., Staton K., et al. In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R)-4-Fluoroglutamine. Radiology. 2018;287:667–675. doi: 10.1148/radiol.2017162610. PubMed DOI PMC

Jiang X., Pei L.-Y., Guo W.-X., Qi X., Lu X.-G. Glutamine Supported Early Enteral Therapy for Severe Acute Pancreatitis: A Systematic Review and Meta-Analysis. Asia Pac. J. Clin. Nutr. 2020;29:253–261. doi: 10.6133/apjcn.202007_29(2).0007. PubMed DOI

Schiliro C., Firestein B.L. Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation. Cells. 2021;10:1056. doi: 10.3390/cells10051056. PubMed DOI PMC

Chang X., Liu X., Wang H., Yang X., Gu Y. Glycolysis in the Progression of Pancreatic Cancer. Am. J. Cancer Res. 2022;12:861–872. PubMed PMC

Yang J., Ren B., Yang G., Wang H., Chen G., You L., Zhang T., Zhao Y. The Enhancement of Glycolysis Regulates Pancreatic Cancer Metastasis. Cell. Mol. Life Sci. 2020;77:305–321. doi: 10.1007/s00018-019-03278-z. PubMed DOI PMC

Liu C., Deng S., Xiao Z., Lu R., Cheng H., Feng J., Shen X., Ni Q., Wu W., Yu X., et al. Glutamine Is a Substrate for Glycosylation and CA19-9 Biosynthesis through Hexosamine Biosynthetic Pathway in Pancreatic Cancer. Discov. Oncol. 2023;14:20. doi: 10.1007/s12672-023-00628-z. PubMed DOI PMC

Dong S., Zhao Z., Li X., Chen Z., Jiang W., Zhou W. Efficacy of Glutamine in Treating Severe Acute Pancreatitis: A Systematic Review and Meta-Analysis. Front. Nutr. 2022;9:865102. doi: 10.3389/fnut.2022.865102. PubMed DOI PMC

Arutla M., Raghunath M., Deepika G., Jakkampudi A., Murthy H.V.V., Rao G.V., Reddy D.N., Talukdar R. Efficacy of Enteral Glutamine Supplementation in Patients with Severe and Predicted Severe Acute Pancreatitis—A Randomized Controlled Trial. Indian J. Gastroenterol. 2019;38:338–347. doi: 10.1007/s12664-019-00962-7. PubMed DOI

Zhou J., Xue Y., Liu Y., Li X.K., Tong Z.H., Li W.Q. The Effect of Immunonutrition in Patients with Acute Pancreatitis: A Systematic Review and Meta-Analysis. J. Hum. Nutr. Diet. 2021;34:429–439. doi: 10.1111/jhn.12816. PubMed DOI

Zhou S., Jin L.-R., He C. Effects of Imipenem Combined with Glutamine in the Treatment of Severe Acute Pancreatitis with Abdominal Infection in Mainland China: A Meta-Analysis. Rev. Assoc. Med. Bras. 2022;68:395–399. doi: 10.1590/1806-9282.20211127. PubMed DOI

Long N.P., Yoon S.J., Anh N.H., Nghi T.D., Lim D.K., Hong Y.J., Hong S.-S., Kwon S.W. A Systematic Review on Metabolomics-Based Diagnostic Biomarker Discovery and Validation in Pancreatic Cancer. Metabolomics. 2018;14:109. doi: 10.1007/s11306-018-1404-2. PubMed DOI

Xiong Y., Shi C., Zhong F., Liu X., Yang P. LC-MS/MS and SWATH Based Serum Metabolomics Enables Biomarker Discovery in Pancreatic Cancer. Clin. Chim. Acta. 2020;506:214–221. doi: 10.1016/j.cca.2020.03.043. PubMed DOI

Borroto-Escuela D.O., Ambrogini P., Chruścicka B., Lindskog M., Crespo-Ramirez M., Hernández-Mondragón J.C., Perez de la Mora M., Schellekens H., Fuxe K. The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects. Int. J. Mol. Sci. 2021;22:1927. doi: 10.3390/ijms22041927. PubMed DOI PMC

Paredes S., Cantillo S., Candido K.D., Knezevic N.N. An Association of Serotonin with Pain Disorders and Its Modulation by Estrogens. Int. J. Mol. Sci. 2019;20:5729. doi: 10.3390/ijms20225729. PubMed DOI PMC

Stasi C., Sadalla S., Milani S. The Relationship Between the Serotonin Metabolism, Gut-Microbiota and the Gut-Brain Axis. Curr. Drug Metab. 2019;20:646–655. doi: 10.2174/1389200220666190725115503. PubMed DOI

Balakrishna P., George S., Hatoum H., Mukherjee S. Serotonin Pathway in Cancer. Int. J. Mol. Sci. 2021;22:1268. doi: 10.3390/ijms22031268. PubMed DOI PMC

Joish V.N., Shah S., Tierce J.C., Patel D., McKee C., Lapuerta P., Zacks J. Serotonin Levels and 1-Year Mortality in Patients with Neuroendocrine Tumors: A Systematic Review and Meta-Analysis. Future Oncol. 2019;15:1397–1406. doi: 10.2217/fon-2018-0960. PubMed DOI

Karmakar S., Lal G. Role of Serotonin Receptor Signaling in Cancer Cells and Anti-Tumor Immunity. Theranostics. 2021;11:5296–5312. doi: 10.7150/thno.55986. PubMed DOI PMC

Sherman S.K., Maxwell J.E., O’Dorisio M.S., O’Dorisio T.M., Howe J.R. Pancreastatin Predicts Survival in Neuroendocrine Tumors. Ann. Surg. Oncol. 2014;21:2971–2980. doi: 10.1245/s10434-014-3728-0. PubMed DOI PMC

Shu X., Zheng W., Yu D., Li H.-L., Lan Q., Yang G., Cai H., Ma X., Rothman N., Gao Y.-T., et al. Prospective Metabolomics Study Identifies Potential Novel Blood Metabolites Associated with Pancreatic Cancer Risk. Int. J. Cancer. 2018;143:2161–2167. doi: 10.1002/ijc.31574. PubMed DOI PMC

Manzo T., Prentice B.M., Anderson K.G., Raman A., Schalck A., Codreanu G.S., Nava Lauson C.B., Tiberti S., Raimondi A., Jones M.A., et al. Accumulation of Long-Chain Fatty Acids in the Tumor Microenvironment Drives Dysfunction in Intrapancreatic CD8+ T Cells. J. Exp. Med. 2020;217:e20191920. doi: 10.1084/jem.20191920. PubMed DOI PMC

Ketavarapu V., Ravikanth V., Sasikala M., Rao G.V., Devi C.V., Sripadi P., Bethu M.S., Amanchy R., Murthy H.V.V., Pandol S.J., et al. Integration of Metabolites from Meta-Analysis with Transcriptome Reveals Enhanced SPHK1 in PDAC with a Background of Pancreatitis. BMC Cancer. 2022;22:792. doi: 10.1186/s12885-022-09816-6. PubMed DOI PMC

Wedekind R., Rothwell J.A., Viallon V., Keski-Rahkonen P., Schmidt J.A., Chajes V., Katzke V., Johnson T., Santucci de Magistris M., Krogh V., et al. Determinants of Blood Acylcarnitine Concentrations in Healthy Individuals of the European Prospective Investigation into Cancer and Nutrition. Clin. Nutr. 2022;41:1735–1745. doi: 10.1016/j.clnu.2022.05.020. PubMed DOI PMC

Feig C., Gopinathan A., Neesse A., Chan D.S., Cook N., Tuveson D.A. The Pancreas Cancer Microenvironment. Clin. Cancer Res. 2012;18:4266–4276. doi: 10.1158/1078-0432.CCR-11-3114. PubMed DOI PMC

Stopa K.B., Kusiak A.A., Szopa M.D., Ferdek P.E., Jakubowska M.A. Pancreatic Cancer and Its Microenvironment—Recent Advances and Current Controversies. Int. J. Mol. Sci. 2020;21:3218. doi: 10.3390/ijms21093218. PubMed DOI PMC

Wei Z., Liu X., Cheng C., Yu W., Yi P. Metabolism of Amino Acids in Cancer. Front. Cell Dev. Biol. 2021;8:603837. doi: 10.3389/fcell.2020.603837. PubMed DOI PMC

Wang W., Cui J., Ma H., Lu W., Huang J. Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine. Front. Oncol. 2021;11:684961. doi: 10.3389/fonc.2021.684961. PubMed DOI PMC

Zang Q., Sun C., Chu X., Li L., Gan W., Zhao Z., Song Y., He J., Zhang R., Abliz Z. Spatially Resolved Metabolomics Combined with Multicellular Tumor Spheroids to Discover Cancer Tissue Relevant Metabolic Signatures. Anal. Chim. Acta. 2021;1155:338342. doi: 10.1016/j.aca.2021.338342. PubMed DOI

Zemanova M., Vecka M., Petruželka L., Staňková B., Žák A., Zeman M. Plasma Phosphatidylcholines Fatty Acids in Men with Squamous Cell Esophageal Cancer: Chemoradiotherapy Improves Abnormal Profile. Med. Sci. Monit. 2016;22:4092–4099. doi: 10.12659/MSM.896799. PubMed DOI PMC

Zang B., Wang W., Wang Y., Li P., Xia T., Liu X., Chen D., Piao H.-L., Qi H., Ma Y. Metabolomic Characterization Reveals ILF2 and ILF3 Affected Metabolic Adaptions in Esophageal Squamous Cell Carcinoma. Front. Mol. Biosci. 2021;8:721990. doi: 10.3389/fmolb.2021.721990. PubMed DOI PMC

Molendijk J., Kolka C.M., Cairns H., Brosda S., Mohamed A., Shah A.K., Brown I., Hodson M.P., Hennessy T., Liu G., et al. Elevation of Fatty Acid Desaturase 2 in Esophageal Adenocarcinoma Increases Polyunsaturated Lipids and May Exacerbate Bile Acid-Induced DNA Damage. Clin. Transl. Med. 2022;12:e810. doi: 10.1002/ctm2.810. PubMed DOI PMC

Mir S.A., Rajagopalan P., Jain A.P., Khan A.A., Datta K.K., Mohan S.V., Lateef S.S., Sahasrabuddhe N., Somani B.L., Keshava Prasad T.S., et al. LC-MS-Based Serum Metabolomic Analysis Reveals Dysregulation of Phosphatidylcholines in Esophageal Squamous Cell Carcinoma. J. Proteom. 2015;127:96–102. doi: 10.1016/j.jprot.2015.05.013. PubMed DOI

Nishiumi S., Fujigaki S., Kobayashi T., Kojima T., Ito Y., Daiko H., Kato K., Shoji H., Kodama Y., Honda K., et al. Metabolomics-Based Discovery of Serum Biomarkers to Predict the Side-Effects of Neoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma. Anticancer Res. 2019;39:519–526. doi: 10.21873/anticanres.13143. PubMed DOI

Ma W., Wang S., Zhang T., Zhang E.Y., Zhou L., Hu C., Yu J.J., Xu G. Activation of Choline Kinase Drives Aberrant Choline Metabolism in Esophageal Squamous Cell Carcinomas. J. Pharm. Biomed. Anal. 2018;155:148–156. doi: 10.1016/j.jpba.2018.03.062. PubMed DOI

Corona G., Cannizzaro R., Miolo G., Caggiari L., De Zorzi M., Repetto O., Steffan A., De Re V. Use of Metabolomics as a Complementary Omic Approach to Implement Risk Criteria for First-Degree Relatives of Gastric Cancer Patients. Int. J. Mol. Sci. 2018;19:750. doi: 10.3390/ijms19030750. PubMed DOI PMC

Jin X., Li H., Li B., Zhang C., He Y. Knockdown and Inhibition of Hydroxytryptamine Receptor 1D Suppress Proliferation and Migration of Gastric Cancer Cells. Biochem. Biophys. Res. Commun. 2022;620:143–149. doi: 10.1016/j.bbrc.2022.06.088. PubMed DOI

Khin P.P., Po W.W., Thein W., Sohn U.D. Apoptotic Effect of Fluoxetine through the Endoplasmic Reticulum Stress Pathway in the Human Gastric Cancer Cell Line AGS. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2020;393:537–549. doi: 10.1007/s00210-019-01739-7. PubMed DOI

Niu Q., Li L., Zhang C., Qi C., He Q., Zhu Y. Expression of 5-HT Relates to Stem Cell Marker LGR5 in Patients with Gastritis and Gastric Cancer. Dig. Dis. Sci. 2023;68:1864–1872. doi: 10.1007/s10620-022-07772-6. PubMed DOI PMC

Zou L., Guo L., Zhu C., Lai Z., Li Z., Yang A. Serum Phospholipids Are Potential Biomarkers for the Early Diagnosis of Gastric Cancer. Clin. Chim. Acta. 2021;519:276–284. doi: 10.1016/j.cca.2021.05.002. PubMed DOI

Zou L., Wang L., Guo L., Zhou W., Lai Z., Zhu C., Wu X., Li Z., Yang A. Small Molecules as Potential Biomarkers of Early Gastric Cancer: A Mass Spectrometry Imaging Approach. Clin. Chim. Acta. 2022;534:35–42. doi: 10.1016/j.cca.2022.06.032. PubMed DOI

Uehara T., Kikuchi H., Miyazaki S., Iino I., Setoguchi T., Hiramatsu Y., Ohta M., Kamiya K., Morita Y., Tanaka H., et al. Overexpression of Lysophosphatidylcholine Acyltransferase 1 and Concomitant Lipid Alterations in Gastric Cancer. Ann. Surg. Oncol. 2016;23((Suppl. 2)):S206–S213. doi: 10.1245/s10434-015-4459-6. PubMed DOI

Guo Y., Ren J., Li X., Liu X., Liu N., Wang Y., Li Z. Simultaneous Quantification of Serum Multi-Phospholipids as Potential Biomarkers for Differentiating Different Pathophysiological States of Lung, Stomach, Intestine, and Pancreas. J. Cancer. 2017;8:2191–2204. doi: 10.7150/jca.19128. PubMed DOI PMC

Huang Q., Tan Y., Yin P., Ye G., Gao P., Lu X., Wang H., Xu G. Metabolic Characterization of Hepatocellular Carcinoma Using Nontargeted Tissue Metabolomics. Cancer Res. 2013;73:4992–5002. doi: 10.1158/0008-5472.CAN-13-0308. PubMed DOI

Okubo H., Ando H., Ishizuka K., Kitagawa R., Okubo S., Saito H., Kokubu S., Miyazaki A., Ikejima K., Shiina S., et al. Carnitine Insufficiency Is Associated with Fatigue during Lenvatinib Treatment in Patients with Hepatocellular Carcinoma. PLoS ONE. 2020;15:e0229772. doi: 10.1371/journal.pone.0229772. PubMed DOI PMC

Padickakudy R., Pereyra D., Offensperger F., Jonas P., Oehlberger L., Schwarz C., Haegele S., Assinger A., Brostjan C., Gruenberger T., et al. Bivalent Role of Intra-Platelet Serotonin in Liver Regeneration and Tumor Recurrence in Humans. J. Hepatol. 2017;67:1243–1252. doi: 10.1016/j.jhep.2017.08.009. PubMed DOI

Niture S., Gyamfi M.A., Kedir H., Arthur E., Ressom H., Deep G., Kumar D. Serotonin Induced Hepatic Steatosis Is Associated with Modulation of Autophagy and Notch Signaling Pathway. Cell Commun. Signal. 2018;16:78. doi: 10.1186/s12964-018-0282-6. PubMed DOI PMC

Yang Q., Yan C., Yin C., Gong Z. Serotonin Activated Hepatic Stellate Cells Contribute to Sex Disparity in Hepatocellular Carcinoma. Cell. Mol. Gastroenterol. Hepatol. 2017;3:484–499. doi: 10.1016/j.jcmgh.2017.01.002. PubMed DOI PMC

Abdel-Hamid N.M., Shehata D.E., Abdel-Ghany A.A., Ragaa A., Wahid A. Serum Serotonin as Unexpected Potential Marker for Staging of Experimental Hepatocellular Carcinoma. Biomed. Pharmacother. 2016;83:407–411. doi: 10.1016/j.biopha.2016.07.005. PubMed DOI

Mamdouh F., Abdel Alem S., Abdo M., Abdelaal A., Salem A., Rabiee A., Elsisi O. Serum Serotonin as a Potential Diagnostic Marker for Hepatocellular Carcinoma. J. Interferon Cytokine Res. 2019;39:780–785. doi: 10.1089/jir.2019.0088. PubMed DOI

Lai S.-W., Hwang B.-F., Liu C.-S., Liao K.-F. Selective Serotonin Reuptake Inhibitor Use and the Risk of Hepatocellular Carcinoma. Eur. J. Clin. Pharmacol. 2022;78:1197–1198. doi: 10.1007/s00228-022-03306-1. PubMed DOI

Huang Y.-H., Yeh C.-T. Anticancer Effects of Antidepressants in Hepatocellular Carcinoma Cells. Anticancer Res. 2023;43:1201–1206. doi: 10.21873/anticanres.16266. PubMed DOI

Abdel-Razik A., Elhelaly R., Elzehery R., El-Diasty A., Abed S., Elhammady D., Tawfik A. Could Serotonin Be a Potential Marker for Hepatocellular Carcinoma? A Prospective Single-Center Observational Study. Eur. J. Gastroenterol. Hepatol. 2016;28:599–605. doi: 10.1097/MEG.0000000000000569. PubMed DOI

Yu L., Zeng Z., Tan H., Feng Q., Zhou Q., Hu J., Li Y., Wang J., Yang W., Feng J., et al. Significant Metabolic Alterations in Patients with Hepatitis B Virus Replication Observed via Serum Untargeted Metabolomics Shed New Light on Hepatitis B Virus Infection. J. Drug Target. 2022;30:442–449. doi: 10.1080/1061186X.2021.2009841. PubMed DOI

Kwee S.A., Sato M.M., Kuang Y., Franke A., Custer L., Miyazaki K., Wong L.L. [18F]Fluorocholine PET/CT Imaging of Liver Cancer: Radiopathologic Correlation with Tissue Phospholipid Profiling. Mol. Imaging Biol. 2017;19:446–455. doi: 10.1007/s11307-016-1020-3. PubMed DOI PMC

Hall Z., Chiarugi D., Charidemou E., Leslie J., Scott E., Pellegrinet L., Allison M., Mocciaro G., Anstee Q.M., Evan G.I., et al. Lipid Remodeling in Hepatocyte Proliferation and Hepatocellular Carcinoma. Hepatology. 2021;73:1028–1044. doi: 10.1002/hep.31391. PubMed DOI

Hou G., Ding D., Tian T., Dong W., Sun D., Liu G., Yang Y., Zhou W. Metabolomics-Based Classification Reveals Subtypes of Hepatocellular Carcinoma. Mol. Carcinog. 2022;61:989–1001. doi: 10.1002/mc.23455. PubMed DOI

Li Z., Guan M., Lin Y., Cui X., Zhang Y., Zhao Z., Zhu J. Aberrant Lipid Metabolism in Hepatocellular Carcinoma Revealed by Liver Lipidomics. Int. J. Mol. Sci. 2017;18:2550. doi: 10.3390/ijms18122550. PubMed DOI PMC

Cotte A.K., Cottet V., Aires V., Mouillot T., Rizk M., Vinault S., Binquet C., de Barros J.-P.P., Hillon P., Delmas D. Phospholipid Profiles and Hepatocellular Carcinoma Risk and Prognosis in Cirrhotic Patients. Oncotarget. 2019;10:2161–2172. doi: 10.18632/oncotarget.26738. PubMed DOI PMC

Ismail I.T., Elfert A., Helal M., Salama I., El-Said H., Fiehn O. Remodeling Lipids in the Transition from Chronic Liver Disease to Hepatocellular Carcinoma. Cancers. 2020;13:88. doi: 10.3390/cancers13010088. PubMed DOI PMC

Ala M. Tryptophan Metabolites Modulate Inflammatory Bowel Disease and Colorectal Cancer by Affecting Immune System. Int. Rev. Immunol. 2022;41:326–345. doi: 10.1080/08830185.2021.1954638. PubMed DOI

Dahabiyeh L.A., Hudaib F., Hourani W., Darwish W., Abu-Irmaileh B., Deb P.K., Venugopala K.N., Mohanlall V., Chandrashekharappa S., Abu-Dahab R., et al. Mass Spectrometry-Based Metabolomics Approach and in Vitro Assays Revealed Promising Role of 2,3-Dihydroquinazolin-4(1H)-One Derivatives against Colorectal Cancer Cell Lines. Eur. J. Pharm. Sci. 2023;182:106378. doi: 10.1016/j.ejps.2023.106378. PubMed DOI

Huang Y.-W., Lin C.-W., Pan P., Echeveste C.E., Dong A., Oshima K., Yearsley M., Yu J., Wang L.-S. Dysregulated Free Fatty Acid Receptor 2 Exacerbates Colonic Adenoma Formation in Apc Min/+ Mice: Relation to Metabolism and Gut Microbiota Composition. J. Cancer Prev. 2021;26:32–40. doi: 10.15430/JCP.2021.26.1.32. PubMed DOI PMC

Wang X., Wang J., Wang Z., Wang Q., Li H. Dynamic Monitoring of Plasma Amino Acids and Carnitine during Chemotherapy of Patients with Alimentary Canal Malignancies and Its Clinical Value. OncoTargets Ther. 2015;8:1989–1996. doi: 10.2147/OTT.S86562. PubMed DOI PMC

Kannen V., Bader M., Sakita J.Y., Uyemura S.A., Squire J.A. The Dual Role of Serotonin in Colorectal Cancer. Trends Endocrinol. Metab. 2020;31:611–625. doi: 10.1016/j.tem.2020.04.008. PubMed DOI

Mao L., Xin F., Ren J., Xu S., Huang H., Zha X., Wen X., Gu G., Yang G., Cheng Y., et al. 5-HT2B-Mediated Serotonin Activation in Enterocytes Suppresses Colitis-Associated Cancer Initiation and Promotes Cancer Progression. Theranostics. 2022;12:3928–3945. doi: 10.7150/thno.70762. PubMed DOI PMC

Shen Y., Sun M., Zhu J., Wei M., Li H., Zhao P., Wang J., Li R., Tian L., Tao Y., et al. Tissue Metabolic Profiling Reveals Major Metabolic Alteration in Colorectal Cancer. Mol. Omics. 2021;17:464–471. doi: 10.1039/D1MO00022E. PubMed DOI

Zhu P., Lu T., Chen Z., Liu B., Fan D., Li C., Wu J., He L., Zhu X., Du Y., et al. 5-Hydroxytryptamine Produced by Enteric Serotonergic Neurons Initiates Colorectal Cancer Stem Cell Self-Renewal and Tumorigenesis. Neuron. 2022;110:2268–2282.e4. doi: 10.1016/j.neuron.2022.04.024. PubMed DOI

Elmallah M.I.Y., Ortega-Deballon P., Hermite L., Pais-De-Barros J.-P., Gobbo J., Garrido C. Lipidomic Profiling of Exosomes from Colorectal Cancer Cells and Patients Reveals Potential Biomarkers. Mol. Oncol. 2022;16:2710–2718. doi: 10.1002/1878-0261.13223. PubMed DOI PMC

Peng S., Li Y., Huang M., Tang G., Xie Y., Chen D., Hu Y., Yu T., Cai J., Yuan Z., et al. Metabolomics Reveals That CAF-Derived Lipids Promote Colorectal Cancer Peritoneal Metastasis by Enhancing Membrane Fluidity. Int. J. Biol. Sci. 2022;18:1912–1932. doi: 10.7150/ijbs.68484. PubMed DOI PMC

Hang D., Zeleznik O.A., Lu J., Joshi A.D., Wu K., Hu Z., Shen H., Clish C.B., Liang L., Eliassen A.H., et al. Plasma Metabolomic Profiles for Colorectal Cancer Precursors in Women. Eur. J. Epidemiol. 2022;37:413–422. doi: 10.1007/s10654-021-00834-5. PubMed DOI PMC

Choi S., Yoo Y.J., Kim H., Lee H., Chung H., Nam M.-H., Moon J.-Y., Lee H.S., Yoon S., Kim W.-Y. Clinical and Biochemical Relevance of Monounsaturated Fatty Acid Metabolism Targeting Strategy for Cancer Stem Cell Elimination in Colon Cancer. Biochem. Biophys. Res. Commun. 2019;519:100–105. doi: 10.1016/j.bbrc.2019.08.137. PubMed DOI

Mika A., Pakiet A., Czumaj A., Kaczynski Z., Liakh I., Kobiela J., Perdyan A., Adrych K., Makarewicz W., Sledzinski T. Decreased Triacylglycerol Content and Elevated Contents of Cell Membrane Lipids in Colorectal Cancer Tissue: A Lipidomic Study. J. Clin. Med. 2020;9:1095. doi: 10.3390/jcm9041095. PubMed DOI PMC

Chen L., Zhang C., Gui Q., Chen Y., Yang Y. Ultra-performance Liquid Chromatography Coupled with Quadrupole Time-of-flight Mass Spectrometry-based Metabolic Profiling of Human Serum Prior to and Following Radical Resection of Colorectal Carcinoma. Mol. Med. Rep. 2015;12:6879–6886. doi: 10.3892/mmr.2015.4289. PubMed DOI