Comprehensive Plasma Metabolomic Profile of Patients with Advanced Neuroendocrine Tumors (NETs). Diagnostic and Biological Relevance

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2021 Jun 2

PMID 34072010

Citations 8

Authors

Beatriz Soldevilla

Angeles Lopez-Lopez

Alberto Lens-Pardo

Carlos Carretero-Puche

Angeles Lopez-Gonzalvez

Anna La Salvia

Beatriz Gil-Calderon

Maria C Riesco-Martinez

Paula Espinosa-Olarte

Jacinto Sarmentero

Beatriz Rubio-Cuesta

Raul Rincon

Coral Barbas

Rocio Garcia-Carbonero

Affiliations

Soon will be listed here.

Abstract

Purpose: High-throughput "-omic" technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential.

Methods: Plasma samples from 77 NETs and 68 controls were profiled by GC-MS, CE-MS and LC-MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential.

Results: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential.

Conclusions: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research.

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References

Larson A, Hedgire S, Deshpande V, Stemmer-Rachamimov A, Harisinghani M, Ferrone C . Pancreatic neuroendocrine tumors in patients with tuberous sclerosis complex. Clin Genet. 2011; 82(6):558-63. DOI: 10.1111/j.1399-0004.2011.01805.x. View

Zabala-Letona A, Arruabarrena-Aristorena A, Martin-Martin N, Fernandez-Ruiz S, Sutherland J, Clasquin M . mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature. 2017; 547(7661):109-113. PMC: 5505479. DOI: 10.1038/nature22964. View

Panagiotopoulos A, Kalyvianaki K, Castanas E, Kampa M . Eicosanoids in prostate cancer. Cancer Metastasis Rev. 2018; 37(2-3):237-243. DOI: 10.1007/s10555-018-9750-0. View

Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, Tanabe M . Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res. 2013; 42(Database issue):D199-205. PMC: 3965122. DOI: 10.1093/nar/gkt1076. View

Huang B, Song B, Xu C . Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab. 2020; 2(2):132-141. DOI: 10.1038/s42255-020-0174-0. View

Gonzalez-Flores E, Serrano R, Sevilla I, Viudez A, Barriuso J, Benavent M . SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2018). Clin Transl Oncol. 2018; 21(1):55-63. PMC: 6339660. DOI: 10.1007/s12094-018-1980-7. View

Kinross J, Drymousis P, Jimenez B, Frilling A . Metabonomic profiling: a novel approach in neuroendocrine neoplasias. Surgery. 2014; 154(6):1185-92. DOI: 10.1016/j.surg.2013.06.018. View

Jewison T, Su Y, Disfany F, Liang Y, Knox C, Maciejewski A . SMPDB 2.0: big improvements to the Small Molecule Pathway Database. Nucleic Acids Res. 2013; 42(Database issue):D478-84. PMC: 3965088. DOI: 10.1093/nar/gkt1067. View

Habibzadeh F, Habibzadeh P, Yadollahie M . On determining the most appropriate test cut-off value: the case of tests with continuous results. Biochem Med (Zagreb). 2016; 26(3):297-307. PMC: 5082211. DOI: 10.11613/BM.2016.034. View

10.

Brandi M, Gagel R, Angeli A, Bilezikian J, Beck-Peccoz P, Bordi C . Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001; 86(12):5658-71. DOI: 10.1210/jcem.86.12.8070. View

11.

Gerner E, Meyskens Jr F . Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer. 2004; 4(10):781-92. DOI: 10.1038/nrc1454. View

12.

Yao J, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E . Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2015; 387(10022):968-977. PMC: 6063317. DOI: 10.1016/S0140-6736(15)00817-X. View

13.

Scarpa A, Chang D, Nones K, Corbo V, Patch A, Bailey P . Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017; 543(7643):65-71. DOI: 10.1038/nature21063. View

14.

Suhre K, Shin S, Petersen A, Mohney R, Meredith D, Wagele B . Human metabolic individuality in biomedical and pharmaceutical research. Nature. 2011; 477(7362):54-60. PMC: 3832838. DOI: 10.1038/nature10354. View

15.

Dudzik D, Zorawski M, Skotnicki M, Zarzycki W, Kozlowska G, Bibik-Malinowska K . Metabolic fingerprint of Gestational Diabetes Mellitus. J Proteomics. 2014; 103:57-71. DOI: 10.1016/j.jprot.2014.03.025. View

16.

Gao B, Lue H, Podolak J, Fan S, Zhang Y, Serawat A . Multi-Omics Analyses Detail Metabolic Reprogramming in Lipids, Carnitines, and Use of Glycolytic Intermediates between Prostate Small Cell Neuroendocrine Carcinoma and Prostate Adenocarcinoma. Metabolites. 2019; 9(5). PMC: 6572715. DOI: 10.3390/metabo9050082. View

17.

Mamani-Huanca M, Gradillas A, de la Fuente A, Lopez-Gonzalvez A, Barbas C . Unveiling the Fragmentation Mechanisms of Modified Amino Acids as the Key for Their Targeted Identification. Anal Chem. 2020; 92(7):4848-4857. DOI: 10.1021/acs.analchem.9b04313. View

18.

La Rosa S, Uccella S, Finzi G, Albarello L, Sessa F, Capella C . Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. Hum Pathol. 2003; 34(1):18-27. DOI: 10.1053/hupa.2003.56. View

19.

Jiao Y, Shi C, Edil B, de Wilde R, Klimstra D, Maitra A . DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011; 331(6021):1199-203. PMC: 3144496. DOI: 10.1126/science.1200609. View

20.

Bertini I, Cacciatore S, Jensen B, Schou J, Johansen J, Kruhoffer M . Metabolomic NMR fingerprinting to identify and predict survival of patients with metastatic colorectal cancer. Cancer Res. 2011; 72(1):356-64. DOI: 10.1158/0008-5472.CAN-11-1543. View