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Cancer Metabolomics 2019
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Cancer Metabolomics 2019

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (25 December 2019) | Viewed by 35244

Special Issue Editor

Dr. Bénédicte Elena-Herrmann

E-Mail Website
Guest Editor
Institute for Advanced Biosciences, University Grenoble Alpes/CNRS/INSERM, Grenoble, France
Interests: cancer metabolomics; molecular epidemiology; metabolism and epigenetics; advanced NMR methods; chemometrics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We welcome the submission of original research articles or review papers as contributions to this Special Issue of Metabolites dedicated to cancer metabolomics. The aim for this Issue is to highlight innovative metabolomic approaches, as well as novel achievements of metabolomic investigations in oncology that either provide mechanistic insights into model systems or pertain to translational and clinical studies. Many aspects of metabolomics research, notably in the field of cancerology, contribute to defining disease trajectories that sustain the promotion of P4 medicine—predictive, preventive, personalized, and participatory—to transform healthcare. We therefore encourage contributions that include cross-disciplinary research, involve large-scale data collection and analysis, or involve multi-omics studies for integrative medicine. Noting that over 50% of all cancers develop in a background of pre-existing infectious, immuno-inflammatory or metabolic chronic disease, original work that aims to understand the underlying metabolic mechanisms linking chronic diseases with cancer will be a highly relevant contribution to this Special Issue. Investigations of metabolic markers of risk, early markers of disease, and prognostic markers of the evolution of responses to cancer treatment are equally welcome.

We hope with this Special Issue to provide our readers with a timely overview of metabolomics contemporary research and perspectives in the broad area of cancerology.

Dr. Bénédicte Elena-Herrmann
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Diagnosis or predictive metabolic markers
  • Tumor metabolism
  • Chronic diseases and cancer
  • Molecular epidemiology of cancer
  • In vivo spectroscopy
  • Model systems

Published Papers (9 papers)

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Research

14 pages, 769 KiB  
Article
1H-NMR Based Serum Metabolomics Identifies Different Profile between Sarcopenia and Cancer Cachexia in Ageing Walker 256 Tumour-Bearing Rats
by Laís Rosa Viana, Leisa Lopes-Aguiar, Rafaela Rossi Rosolen, Rogerio Willians dos Santos and Maria Cristina Cintra Gomes-Marcondes
Metabolites 2020, 10(4), 161; https://doi.org/10.3390/metabo10040161 - 21 Apr 2020
Cited by 4 | Viewed by 2685
Abstract
Sarcopenia among the older population has been growing over the last few years. In addition, the incidence of cancers increases with age and, consequently, the development of cachexia related cancer. Therefore, the elucidation of the metabolic derangements of sarcopenia and cachexia are important [...] Read more.
Sarcopenia among the older population has been growing over the last few years. In addition, the incidence of cancers increases with age and, consequently, the development of cachexia related cancer. Therefore, the elucidation of the metabolic derangements of sarcopenia and cachexia are important to improve the survival and life quality of cancer patients. We performed the 1H-NMR based serum metabolomics in adult (A) and ageing (S) Walker 256 tumour-bearing rats in different stages of tumour evolution, namely intermediated (Wi) and advanced (Wa). Among 52 serum metabolites that were identified, 21 were significantly increased in S and 14 and 19 decreased in the Wi and Wa groups, respectively. The most impacted pathways by this metabolic alteration were related by amino acid biosynthesis and metabolism, with an upregulation in S group and downregulation in Wi and Wa groups. Taken together, our results suggest that the increase in metabolic profile in ageing rats is associated with the higher muscle protein degradation that releases several metabolites, especially amino acids into the serum. On the other hand, we hypothesise that the majority of metabolites released by muscle catabolism are used by tumours to sustain rapid cell proliferation and tumorigenesis. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2019)
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17 pages, 4997 KiB  
Article
Analysis and Simulation of Glioblastoma Cell Lines-Derived Extracellular Vesicles Metabolome
by Miroslava Čuperlović-Culf, Nam H. Khieu, Anuradha Surendra, Melissa Hewitt, Claudie Charlebois and Jagdeep K. Sandhu
Metabolites 2020, 10(3), 88; https://doi.org/10.3390/metabo10030088 - 02 Mar 2020
Cited by 27 | Viewed by 4135
Abstract
Glioblastoma (GBM) is one of the most aggressive cancers of the central nervous system. Despite current advances in non-invasive imaging and the advent of novel therapeutic modalities, patient survival remains very low. There is a critical need for the development of effective biomarkers [...] Read more.
Glioblastoma (GBM) is one of the most aggressive cancers of the central nervous system. Despite current advances in non-invasive imaging and the advent of novel therapeutic modalities, patient survival remains very low. There is a critical need for the development of effective biomarkers for GBM diagnosis and therapeutic monitoring. Extracellular vesicles (EVs) produced by GBM tumors have been shown to play an important role in cellular communication and modulation of the tumor microenvironment. As GBM-derived EVs contain specific “molecular signatures” of their parental cells and are able to transmigrate across the blood–brain barrier into biofluids such as the blood and cerebrospinal fluid (CSF), they are considered as a valuable source of potential diagnostic biomarkers. Given the relatively harsh extracellular environment of blood and CSF, EVs have to endure and adapt to different conditions. The ability of EVs to adjust and function depends on their lipid bilayer, metabolic content and enzymes and transport proteins. The knowledge of EVs metabolic characteristics and adaptability is essential for their utilization as diagnostic and therapeutic tools. The main aim of this study was to determine the metabolome of small EVs or exosomes derived from different GBM cells and compare to the metabolic profile of their parental cells using NMR spectroscopy. In addition, a possible flux of metabolic processes in GBM-derived EVs was simulated using constraint-based modeling from published proteomics information. Our results showed a clear difference between the metabolic profiles of GBM cells, EVs and media. Machine learning analysis of EV metabolomics, as well as flux simulation, supports the notion of active metabolism within EVs, including enzymatic reactions and the transfer of metabolites through the EV membrane. These results are discussed in the context of novel GBM diagnostics and therapeutic monitoring. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2019)
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14 pages, 1394 KiB  
Article
Metabolomics of Small Intestine Neuroendocrine Tumors and Related Hepatic Metastases
by Alessio Imperiale, Gilles Poncet, Pietro Addeo, Elisa Ruhland, Colette Roche, Stephanie Battini, A. Ercument Cicek, Marie Pierrette Chenard, Valérie Hervieu, Bernard Goichot, Philippe Bachellier, Thomas Walter and Izzie Jacques Namer
Metabolites 2019, 9(12), 300; https://doi.org/10.3390/metabo9120300 - 11 Dec 2019
Cited by 8 | Viewed by 3111
Abstract
To assess the metabolomic fingerprint of small intestine neuroendocrine tumors (SI-NETs) and related hepatic metastases, and to investigate the influence of the hepatic environment on SI-NETs metabolome. Ninety-four tissue samples, including 46 SI-NETs, 18 hepatic NET metastases and 30 normal SI and liver [...] Read more.
To assess the metabolomic fingerprint of small intestine neuroendocrine tumors (SI-NETs) and related hepatic metastases, and to investigate the influence of the hepatic environment on SI-NETs metabolome. Ninety-four tissue samples, including 46 SI-NETs, 18 hepatic NET metastases and 30 normal SI and liver samples, were analyzed using 1H-magic angle spinning (HRMAS) NMR nuclear magnetic resonance (NMR) spectroscopy. Twenty-seven metabolites were identified and quantified. Differences between primary NETs vs. normal SI and primary NETs vs. hepatic metastases, were assessed. Network analysis was performed according to several clinical and pathological features. Succinate, glutathion, taurine, myoinositol and glycerophosphocholine characterized NETs. Normal SI specimens showed higher levels of alanine, creatine, ethanolamine and aspartate. PLS-DA revealed a continuum-like distribution among normal SI, G1-SI-NETs and G2-SI-NETs. The G2-SI-NET distribution was closer and clearly separated from normal SI tissue. Lower concentration of glucose, serine and glycine, and increased levels of choline-containing compounds, taurine, lactate and alanine, were found in SI-NETs with more aggressive tumors. Higher abundance of acetate, succinate, choline, phosphocholine, taurine, lactate and aspartate discriminated liver metastases from normal hepatic parenchyma. Higher levels of alanine, ethanolamine, glycerophosphocholine and glucose was found in hepatic metastases than in primary SI-NETs. The present work gives for the first time a snapshot of the metabolomic characteristics of SI-NETs, suggesting the existence of complex metabolic reality, maybe characteristic of different tumor evolution. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2019)
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15 pages, 2952 KiB  
Article
A New Classification Method of Metastatic Cancers Using a 1H-NMR-Based Approach: A Study Case of Melanoma, Breast, and Prostate Cancer Cell Lines
by Corentin Schepkens, Matthieu Dallons, Jonas Dehairs, Ali Talebi, Jérôme Jeandriens, Lise-Marie Drossart, Guillaume Auquier, Vanessa Tagliatti, Johannes V. Swinnen and Jean-Marie Colet
Metabolites 2019, 9(11), 281; https://doi.org/10.3390/metabo9110281 - 17 Nov 2019
Cited by 5 | Viewed by 4707
Abstract
In this study, metastatic melanoma, breast, and prostate cancer cell lines were analyzed using a 1H-NMR-based approach in order to investigate common features and differences of aggressive cancers metabolomes. For that purpose, 1H-NMR spectra of both cellular extracts and culture media [...] Read more.
In this study, metastatic melanoma, breast, and prostate cancer cell lines were analyzed using a 1H-NMR-based approach in order to investigate common features and differences of aggressive cancers metabolomes. For that purpose, 1H-NMR spectra of both cellular extracts and culture media were combined with multivariate data analysis, bringing to light no less than 20 discriminant metabolites able to separate the metastatic metabolomes. The supervised approach succeeded in classifying the metastatic cell lines depending on their glucose metabolism, more glycolysis-oriented in the BRAF proto-oncogene mutated cell lines compared to the others. Other adaptive metabolic features also contributed to the classification, such as the increased total choline content (tCho), UDP-GlcNAc detection, and various changes in the glucose-related metabolites tree, giving additional information about the metastatic metabolome status and direction. Finally, common metabolic features detected via 1H-NMR in the studied cancer cell lines are discussed, identifying the glycolytic pathway, Kennedy’s pathway, and the glutaminolysis as potential and common targets in metastasis, opening up new avenues to cure cancer. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2019)
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17 pages, 3910 KiB  
Article
Untargeted Urinary 1H NMR-Based Metabolomic Pattern as a Potential Platform in Breast Cancer Detection
by Catarina L. Silva, Ana Olival, Rosa Perestrelo, Pedro Silva, Helena Tomás and José S. Câmara
Metabolites 2019, 9(11), 269; https://doi.org/10.3390/metabo9110269 - 07 Nov 2019
Cited by 23 | Viewed by 4332
Abstract
Breast cancer (BC) remains the second leading cause of death among women worldwide. An emerging approach based on the identification of endogenous metabolites (EMs) and the establishment of the metabolomic fingerprint of biological fluids constitutes a new frontier in medical diagnostics and a [...] Read more.
Breast cancer (BC) remains the second leading cause of death among women worldwide. An emerging approach based on the identification of endogenous metabolites (EMs) and the establishment of the metabolomic fingerprint of biological fluids constitutes a new frontier in medical diagnostics and a promising strategy to differentiate cancer patients from healthy individuals. In this work we aimed to establish the urinary metabolomic patterns from 40 BC patients and 38 healthy controls (CTL) using proton nuclear magnetic resonance spectroscopy (1H-NMR) as a powerful approach to identify a set of BC-specific metabolites which might be employed in the diagnosis of BC. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was applied to a 1H-NMR processed data matrix. Metabolomic patterns distinguished BC from CTL urine samples, suggesting a unique metabolite profile for each investigated group. A total of 10 metabolites exhibited the highest contribution towards discriminating BC patients from healthy controls (variable importance in projection (VIP) >1, p < 0.05). The discrimination efficiency and accuracy of the urinary EMs were ascertained by receiver operating characteristic curve (ROC) analysis that allowed the identification of some metabolites with the highest sensitivities and specificities to discriminate BC patients from healthy controls (e.g. creatine, glycine, trimethylamine N-oxide, and serine). The metabolomic pathway analysis indicated several metabolism pathway disruptions, including amino acid and carbohydrate metabolisms, in BC patients, namely, glycine and butanoate metabolisms. The obtained results support the high throughput potential of NMR-based urinary metabolomics patterns in discriminating BC patients from CTL. Further investigations could unravel novel mechanistic insights into disease pathophysiology, monitor disease recurrence, and predict patient response towards therapy. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2019)
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16 pages, 1871 KiB  
Article
The Effects of Doxorubicin-based Chemotherapy and Omega-3 Supplementation on Mouse Brain Lipids
by Djawed Bennouna, Melissa Solano, Tonya S. Orchard, A. Courtney DeVries, Maryam Lustberg and Rachel E. Kopec
Metabolites 2019, 9(10), 208; https://doi.org/10.3390/metabo9100208 - 29 Sep 2019
Cited by 4 | Viewed by 3125
Abstract
Chemotherapy-induced cognitive impairment affects ~30% of breast cancer survivors, but the effects on how chemotherapy impacts brain lipids, and how omega-3 polyunsaturated fatty acid supplementation may confer protection, is unknown. Ovariectomized mice were randomized to two rounds of injections of doxorubicin + cyclophosphamide [...] Read more.
Chemotherapy-induced cognitive impairment affects ~30% of breast cancer survivors, but the effects on how chemotherapy impacts brain lipids, and how omega-3 polyunsaturated fatty acid supplementation may confer protection, is unknown. Ovariectomized mice were randomized to two rounds of injections of doxorubicin + cyclophosphamide or vehicle after consuming a diet supplemented with 2% or 0% EPA+DHA, and sacrificed 4, 7, and 14 days after the last injection (study 1, n = 120) or sacrificed 10 days after the last injection (study 2, n = 40). Study 1 whole brain samples were extracted and analyzed by UHPLC-MS/MS to quantify specialized pro-resolving mediators (SPMs). Lipidomics analyses were performed on hippocampal extracts from study 2 to determine changes in the brain lipidome. Study 1 results: only resolvin D1 was present in all samples, but no differences in concentration were observed (P > 0.05). Study 2 results: chemotherapy was positively correlated with omega-9 fatty acids, and EPA+DHA supplementation helped to maintain levels of plasmalogens. No statistically significant chemotherapy*diet effect was observed. Results demonstrate a limited role of SPMs in the brain post-chemotherapy, but a significant alteration of hippocampal lipids previously associated with other models of cognitive impairment (i.e., Alzheimer’s and Parkinson’s disease). Full article
(This article belongs to the Special Issue Cancer Metabolomics 2019)
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13 pages, 2137 KiB  
Article
Urinary Metabolomics Validates Metabolic Differentiation Between Renal Cell Carcinoma Stages and Reveals a Unique Metabolic Profile for Oncocytomas
by Oluyemi S. Falegan, Shanna A. Arnold Egloff, Andries Zijlstra, M. Eric Hyndman and Hans J. Vogel
Metabolites 2019, 9(8), 155; https://doi.org/10.3390/metabo9080155 - 24 Jul 2019
Cited by 11 | Viewed by 4517
Abstract
Renal cell carcinoma (RCC) is a heterogeneous malignancy which often develops and progresses asymptomatically. Benign oncocytomas are morphologically similar to malignant chromophobe RCC and distinguishing between these two forms on cross-sectional imaging remains a challenge. Therefore, RCC-specific biomarkers are urgently required for accurate [...] Read more.
Renal cell carcinoma (RCC) is a heterogeneous malignancy which often develops and progresses asymptomatically. Benign oncocytomas are morphologically similar to malignant chromophobe RCC and distinguishing between these two forms on cross-sectional imaging remains a challenge. Therefore, RCC-specific biomarkers are urgently required for accurate and non-invasive, pre-surgical diagnosis of benign lesions. We have previously shown that dysregulation in glycolytic and tricarboxylic acid cycle intermediates can distinguish benign lesions from RCC in a stage-specific manner. In this study, preoperative fasting urine samples from patients with renal masses were assessed by ¹H nuclear magnetic resonance (NMR). Significant alterations in levels of tricarboxylic acid cycle intermediates, carnitines and its derivatives were detected in RCC relative to benign masses and in oncocytomas vs. chromophobe RCC. Orthogonal Partial Least Square Discriminant Analysis plots confirmed stage discrimination between benign vs. pT1 (R2 = 0.42, Q2 = 0.27) and benign vs. pT3 (R2 = 0.48, Q2 = 0.32) and showed separation for oncocytomas vs. chromophobe RCC (R2 = 0.81, Q2 = 0.57) and oncocytomas vs. clear cell RCC (R2 = 0.32, Q2 = 0.20). This study validates our previously described metabolic profile distinguishing benign tumors from RCC and presents a novel metabolic signature for oncocytomas which may be exploited for diagnosis before cross-sectional imaging. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2019)
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14 pages, 9836 KiB  
Article
Defining Metabolic Rewiring in Lung Squamous Cell Carcinoma
by Rachel Paes de Araújo, Natália Bertoni, Ana L. Seneda, Tainara F. Felix, Márcio Carvalho, Keir E. Lewis, Érica N. Hasimoto, Manfred Beckmann, Sandra A. Drigo, Patricia P. Reis and Luis A. J. Mur
Metabolites 2019, 9(3), 47; https://doi.org/10.3390/metabo9030047 - 07 Mar 2019
Cited by 7 | Viewed by 4596
Abstract
Metabolomics based on untargeted flow infusion electrospray ionization high-resolution mass spectrometry (FIE-HRMS) can provide a snap-shot of metabolism in living cells. Lung Squamous Cell Carcinoma (SCC) is one of the predominant subtypes of Non-Small Cell Lung Cancers (NSCLCs), which usually shows a poor [...] Read more.
Metabolomics based on untargeted flow infusion electrospray ionization high-resolution mass spectrometry (FIE-HRMS) can provide a snap-shot of metabolism in living cells. Lung Squamous Cell Carcinoma (SCC) is one of the predominant subtypes of Non-Small Cell Lung Cancers (NSCLCs), which usually shows a poor prognosis. We analysed lung SCC samples and matched histologically normal lung tissues from eight patients. Metabolites were profiled by FIE-HRMS and assessed using t-test and principal component analysis (PCA). Differentially accumulating metabolites were mapped to pathways using the mummichog algorithm in R, and biologically meaningful patterns were indicated by Metabolite Set Enrichment Analysis (MSEA). We identified metabolic rewiring networks, including the suppression of the oxidative pentose pathway and found that the normal tricarboxylic acid (TCA) cycle were decoupled from increases in glycolysis and glutamine reductive carboxylation. Well-established associated effects on nucleotide, amino acid and thiol metabolism were also seen. Novel aspects in SCC tissue were increased in Vitamin B complex cofactors, serotonin and a reduction of γ-aminobutyric acid (GABA). Our results show the value of FIE-HRMS as a high throughput screening method that could be exploited in clinical contexts. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2019)
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15 pages, 2971 KiB  
Article
Crosstalk between Metabolic Alterations and Altered Redox Balance in PTC-Derived Cell Lines
by Laura Tronci, Paola Caria, Daniela Virginia Frau, Sonia Liggi, Cristina Piras, Federica Murgia, Maria Laura Santoru, Monica Pibiri, Monica Deiana, Julian Leether Griffin, Roberta Vanni and Luigi Atzori
Metabolites 2019, 9(2), 23; https://doi.org/10.3390/metabo9020023 - 01 Feb 2019
Cited by 7 | Viewed by 3498
Abstract
Background: Thyroid cancer is the most common endocrine malignancy, with papillary thyroid carcinoma (PTC) being the most common (85–90%) among all the different types of thyroid carcinomas. Cancer cells show metabolic alterations and, due to their rapid proliferation, an accumulation of reactive [...] Read more.
Background: Thyroid cancer is the most common endocrine malignancy, with papillary thyroid carcinoma (PTC) being the most common (85–90%) among all the different types of thyroid carcinomas. Cancer cells show metabolic alterations and, due to their rapid proliferation, an accumulation of reactive oxygen species, playing a fundamental role in cancer development and progression. Currently, the crosstalk among thyrocytes metabolism, redox balance and oncogenic mutations remain poorly characterized. The aim of this study was to investigate the interplay among metabolic alterations, redox homeostasis and oncogenic mutations in PTC-derived cells. Methods: Metabolic and redox profile, glutamate-cysteine ligase, glutaminase-1 and metabolic transporters were evaluated in PTC-derived cell lines with distinguished genetic background (TPC-1, K1 and B-CPAP), as well as in an immortalized thyroid cell line (Nthy-ori3-1) selected as control. Results: PTC-derived cells, particularly B-CPAP cells, harboring BRAF, TP53 and human telomerase reverse transcriptase (hTERT) mutation, displayed an increase of metabolites and transporters involved in energetic pathways. Furthermore, all PTC-derived cells showed altered redox homeostasis, as reported by the decreased antioxidant ratios, as well as the increased levels of intracellular oxidant species. Conclusion: Our findings confirmed the pivotal role of the metabolism and redox state regulation in the PTC biology. Particularly, the most perturbed metabolic phenotypes were found in B-CPAP cells, which are characterized by the most aggressive genetic background. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2019)
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