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Metabolites
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Cancer Metabolomics 2018
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Cancer Metabolomics 2018

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 (31 December 2018) | Viewed by 58823

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Paula Guedes de Pinho

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Guest Editor
UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Interests: metabolomics; urological cancers; toxicology; toxicometabolomics; drugs of abuse
Special Issues, Collections and Topics in MDPI journals
Dr. Márcia Carvalho

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Guest Editor
Faculty of Health Sciences, University Fernando Pessoa, Rua Carlos da Maia, 4200-150 Porto, Portugal
Interests: toxicology; drugs of abuse; amphetamines; synthetic cathinones; psychoactive substances; toxicometabolomics; cancer metabolomics; biomarkers; hepatotoxicity; nephrotoxicity; cardiotoxicity; oxidative stress
Special Issues, Collections and Topics in MDPI journals
Dr. Joana Pinto

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Guest Editor
Associate Laboratory i4HB-Institute for Health and Bioeconomy and UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Interests: targeted and untargeted metabolomics; GC-MS; NMR; biomarker discovery; disease detection; treatment response; precision medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The metabolomics approach, defined as the study of all endogenously-produced low-molecular-weight compounds, appeared as a promising strategy to define new cancer biomarkers. Information obtained from metabolomic data can help to highlight disrupted cellular pathways and, consequently, contribute to the development of new-targeted therapies and the optimization of therapeutics. Therefore, metabolomic research may be more clinically translatable than other omics approaches, since metabolites are closely related to the phenotype and the metabolome is sensitive to many factors. Metabolomics seems promising to identify key metabolic pathways characterizing features of pathological and physiological states. Thus, knowing that tumor metabolism markedly differs from the metabolism of normal cells, the use of metabolomics is ideally suited for biomarker research. Some works have already focused on the application of metabolomic approaches to different cancers, namely lung, breast and liver, using urine, exhaled breath, and blood. In this Special Issue we aim to contribute a more complete understanding of cancer disease by using metabolomics approaches. We would like to invite you for your contribution in this Special Issue dedicated to “Cancer Metabolomics”. This Special Issue will be of a great help for all researchers working in this field.

Dr. Paula Guedes de Pinho
Prof. Dr. Márcia Carvalho
Dr. Joana Pinto
Guest Editors

Manuscript Submission Information

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Keywords

  • untargeted metabolomics (data management, data processing and statistical analysis)
  • NMR and MS analytical platforms
  • translatability of model systems (cell lines, tumor tissues) to human biofluids
  • cancer biomarkers
  • validation of biomarkers in biofluids

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Published Papers (9 papers)

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Research

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21 pages, 4854 KiB  
Article
Delta-Tocotrienol Modulates Glutamine Dependence by Inhibiting ASCT2 and LAT1 Transporters in Non-Small Cell Lung Cancer (NSCLC) Cells: A Metabolomic Approach
by Lichchavi Dhananjaya Rajasinghe, Melanie Hutchings and Smiti Vaid Gupta
Metabolites 2019, 9(3), 50; https://doi.org/10.3390/metabo9030050 - 13 Mar 2019
Cited by 25 | Viewed by 5647
Abstract
The growth and development of non-small cell lung cancer (NSCLC) primarily depends on glutamine. Both glutamine and essential amino acids (EAAs) have been reported to upregulate mTOR in NSCLC, which is a bioenergetics sensor involved in the regulation of cell growth, cell survival, [...] Read more.
The growth and development of non-small cell lung cancer (NSCLC) primarily depends on glutamine. Both glutamine and essential amino acids (EAAs) have been reported to upregulate mTOR in NSCLC, which is a bioenergetics sensor involved in the regulation of cell growth, cell survival, and protein synthesis. Seen as novel concepts in cancer development, ASCT2 and LAT transporters allow glutamine and EAAs to enter proliferating tumors as well as send a regulatory signal to mTOR. Blocking or downregulating these glutamine transporters in order to inhibit glutamine uptake would be an excellent therapeutic target for treatment of NSCLC. This study aimed to validate the metabolic dysregulation of glutamine and its derivatives in NSCLC using cellular 1H-NMR metabolomic approach while exploring the mechanism of delta-tocotrienol (δT) on glutamine transporters, and mTOR pathway. Cellular metabolomics analysis showed significant inhibition in the uptake of glutamine, its derivatives glutamate and glutathione, and some EAAs in both cell lines with δT treatment. Inhibition of glutamine transporters (ASCT2 and LAT1) and mTOR pathway proteins (P-mTOR and p-4EBP1) was evident in Western blot analysis in a dose-dependent manner. Our findings suggest that δT inhibits glutamine transporters, thus inhibiting glutamine uptake into proliferating cells, which results in the inhibition of cell proliferation and induction of apoptosis via downregulation of the mTOR pathway. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2018)
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11 pages, 952 KiB  
Article
GC-MS Metabolomics Reveals Distinct Profiles of Low- and High-Grade Bladder Cancer Cultured Cells
by Daniela Rodrigues, Joana Pinto, Ana Margarida Araújo, Carmen Jerónimo, Rui Henrique, Maria de Lourdes Bastos, Paula Guedes de Pinho and Márcia Carvalho
Metabolites 2019, 9(1), 18; https://doi.org/10.3390/metabo9010018 - 18 Jan 2019
Cited by 21 | Viewed by 5056
Abstract
Previous studies have shown that metabolomics can be a useful tool to better understand the mechanisms of carcinogenesis; however, alterations in biochemical pathways that lead to bladder cancer (BC) development have hitherto not been fully investigated. In this study, gas chromatography-mass spectrometry (GC-MS)-based [...] Read more.
Previous studies have shown that metabolomics can be a useful tool to better understand the mechanisms of carcinogenesis; however, alterations in biochemical pathways that lead to bladder cancer (BC) development have hitherto not been fully investigated. In this study, gas chromatography-mass spectrometry (GC-MS)-based metabolomics was applied to unveil the metabolic alterations between low-grade and high-grade BC cultured cell lines. Multivariable analysis revealed a panel of metabolites responsible for the separation between the two tumorigenic cell lines. Significantly lower levels of fatty acids, including myristic, palmitic, and palmitoleic acids, were found in high-grade versus low-grade BC cells. Furthermore, significantly altered levels of some amino acids were observed between low- and high-grade BC, namely glycine, leucine, methionine, valine, and aspartic acid. This study successfully demonstrated the potential of metabolomic analysis to discriminate BC cells according to tumor aggressiveness. Moreover, these findings suggest that bladder tumorigenic cell lines of different grades disclose distinct metabolic profiles, mainly affecting fatty acid biosynthesis and amino acid metabolism to compensate for higher energetic needs. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2018)
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13 pages, 2531 KiB  
Article
Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer
by Thomas D. Horvath, Wai Kin Chan, Michael A. Pontikos, Leona A. Martin, Di Du, Lin Tan, Marina Konopleva, John N. Weinstein and Philip L. Lorenzi
Metabolites 2019, 9(1), 10; https://doi.org/10.3390/metabo9010010 - 9 Jan 2019
Cited by 12 | Viewed by 4944
Abstract
l-asparaginase (ASNase) is a metabolism-targeted anti-neoplastic agent used to treat acute lymphoblastic leukemia (ALL). ASNase’s anticancer activity results from the enzymatic depletion of asparagine (Asn) and glutamine (Gln), which are converted to aspartic acid (Asp) and glutamic acid (Glu), respectively, in the [...] Read more.
l-asparaginase (ASNase) is a metabolism-targeted anti-neoplastic agent used to treat acute lymphoblastic leukemia (ALL). ASNase’s anticancer activity results from the enzymatic depletion of asparagine (Asn) and glutamine (Gln), which are converted to aspartic acid (Asp) and glutamic acid (Glu), respectively, in the blood. Unfortunately, accurate assessment of the in vivo pharmacodynamics (PD) of ASNase is challenging because of the following reasons: (i) ASNase is resilient to deactivation; (ii) ASNase catalytic efficiency is very high; and (iii) the PD markers Asn and Gln are depleted ex vivo in blood samples containing ASNase. To address those issues and facilitate longitudinal studies in individual mice for ASNase PD studies, we present here a new LC-MS/MS bioanalytical method that incorporates rapid quenching of ASNase for measurement of Asn, Asp, Gln, and Glu in just 10 µL of whole blood, with limits of detection (s:n ≥ 10:1) estimated to be 2.3, 3.5, 0.8, and 0.5 µM, respectively. We tested the suitability of the method in a 5-day, longitudinal PD study in mice and found the method to be simple to perform with sufficient accuracy and precision for whole blood measurements. Overall, the method increases the density of data that can be acquired from a single animal and will facilitate optimization of novel ASNase treatment regimens and/or the development of new ASNase variants with desired kinetic properties. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2018)
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13 pages, 3983 KiB  
Article
Dynamic Metabolic Response to Adriamycin-Induced Senescence in Breast Cancer Cells
by Rong You, Jin Dai, Ping Zhang, Gregory A. Barding, Jr. and Daniel Raftery
Metabolites 2018, 8(4), 95; https://doi.org/10.3390/metabo8040095 - 15 Dec 2018
Cited by 21 | Viewed by 4665
Abstract
Cellular senescence displays a heterogeneous set of phenotypes linked to tumor suppression; however, after drug treatment, senescence may also be involved in stable or recurrent cancer. Metabolic changes during senescence can provide detailed information on cellular status and may also have implications for [...] Read more.
Cellular senescence displays a heterogeneous set of phenotypes linked to tumor suppression; however, after drug treatment, senescence may also be involved in stable or recurrent cancer. Metabolic changes during senescence can provide detailed information on cellular status and may also have implications for the development of effective treatment strategies. The metabolic response to Adriamycin (ADR) treatment, which causes senescence as well as cell death, was obtained with the aid of metabolic profiling and isotope tracing in two human breast cancer cell lines, MCF7 and MDA-MB-231. After 5 days of ADR treatment, more than 60% of remaining, intact cells entered into a senescent state, characterized by enlarged and flattened morphology and positive blue staining using SA-β-gal. Metabolic trajectory analysis showed that the two cell lines’ responses were significantly different and were divided into two distinct stages. The metabolic shift from the first stage to the second was reflected by a partial recovery of the TCA cycle, as well as amino acid and lipid metabolisms. Isotope tracing analysis indicated that the higher level of glutamine metabolism helped maintain senescence. The results suggest that the dynamic changes during senescence indicate a multi-step process involving important metabolic pathways which might allow breast cancer cells to adapt to persistent ADR treatment, while the higher level of anapleurosis may be important for maintaining the senescent state. Ultimately, a better understanding of metabolic changes during senescence might provide targets for cancer therapy and tumor eradication. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2018)
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Review

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31 pages, 1860 KiB  
Review
Breast Cancer Metabolomics: From Analytical Platforms to Multivariate Data Analysis. A Review
by Catarina Silva, Rosa Perestrelo, Pedro Silva, Helena Tomás and José S. Câmara
Metabolites 2019, 9(5), 102; https://doi.org/10.3390/metabo9050102 - 22 May 2019
Cited by 54 | Viewed by 7401
Abstract
Cancer is a major health issue worldwide for many years and has been increasing significantly. Among the different types of cancer, breast cancer (BC) remains the leading cause of cancer-related deaths in women being a disease caused by a combination of genetic and [...] Read more.
Cancer is a major health issue worldwide for many years and has been increasing significantly. Among the different types of cancer, breast cancer (BC) remains the leading cause of cancer-related deaths in women being a disease caused by a combination of genetic and environmental factors. Nowadays, the available diagnostic tools have aided in the early detection of BC leading to the improvement of survival rates. However, better detection tools for diagnosis and disease monitoring are still required. In this sense, metabolomic NMR, LC-MS and GC-MS-based approaches have gained attention in this field constituting powerful tools for the identification of potential biomarkers in a variety of clinical fields. In this review we will present the current analytical platforms and their applications to identify metabolites with potential for BC biomarkers based on the main advantages and advances in metabolomics research. Additionally, chemometric methods used in metabolomics will be highlighted. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2018)
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17 pages, 705 KiB  
Review
Critical Review of Volatile Organic Compound Analysis in Breath and In Vitro Cell Culture for Detection of Lung Cancer
by Zhunan Jia, Abhijeet Patra, Viknish Krishnan Kutty and Thirumalai Venkatesan
Metabolites 2019, 9(3), 52; https://doi.org/10.3390/metabo9030052 - 18 Mar 2019
Cited by 144 | Viewed by 9084
Abstract
Breath analysis is a promising technique for lung cancer screening. Despite the rapid development of breathomics in the last four decades, no consistent, robust, and validated volatile organic compound (VOC) signature for lung cancer has been identified. This review summarizes the identified VOC [...] Read more.
Breath analysis is a promising technique for lung cancer screening. Despite the rapid development of breathomics in the last four decades, no consistent, robust, and validated volatile organic compound (VOC) signature for lung cancer has been identified. This review summarizes the identified VOC biomarkers from both exhaled breath analysis and in vitro cultured lung cell lines. Both clinical and in vitro studies have produced inconsistent, and even contradictory, results. Methodological issues that lead to these inconsistencies are reviewed and discussed in detail. Recommendations on addressing specific issues for more accurate biomarker studies have also been made. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2018)
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19 pages, 497 KiB  
Review
Metabolomics Contributions to the Discovery of Prostate Cancer Biomarkers
by Nuria Gómez-Cebrián, Ayelén Rojas-Benedicto, Arturo Albors-Vaquer, José Antonio López-Guerrero, Antonio Pineda-Lucena and Leonor Puchades-Carrasco
Metabolites 2019, 9(3), 48; https://doi.org/10.3390/metabo9030048 - 8 Mar 2019
Cited by 46 | Viewed by 5071
Abstract
Prostate cancer (PCa) is one of the most frequently diagnosed cancers and a leading cause of death among men worldwide. Despite extensive efforts in biomarker discovery during the last years, currently used clinical biomarkers are still lacking enough specificity and sensitivity for PCa [...] Read more.
Prostate cancer (PCa) is one of the most frequently diagnosed cancers and a leading cause of death among men worldwide. Despite extensive efforts in biomarker discovery during the last years, currently used clinical biomarkers are still lacking enough specificity and sensitivity for PCa early detection, patient prognosis, and monitoring. Therefore, more precise biomarkers are required to improve the clinical management of PCa patients. In this context, metabolomics has shown to be a promising and powerful tool to identify novel PCa biomarkers in biofluids. Thus, changes in polyamines, tricarboxylic acid (TCA) cycle, amino acids, and fatty acids metabolism have been reported in different studies analyzing PCa patients’ biofluids. The review provides an up-to-date summary of the main metabolic alterations that have been described in biofluid-based studies of PCa patients, as well as a discussion regarding their potential to improve clinical PCa diagnosis and prognosis. Furthermore, a summary of the most significant findings reported in these studies and the connections and interactions between the different metabolic changes described has also been included, aiming to better describe the specific metabolic signature associated to PCa. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2018)
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21 pages, 631 KiB  
Review
Function, Detection and Alteration of Acylcarnitine Metabolism in Hepatocellular Carcinoma
by Shangfu Li, Dan Gao and Yuyang Jiang
Metabolites 2019, 9(2), 36; https://doi.org/10.3390/metabo9020036 - 21 Feb 2019
Cited by 122 | Viewed by 9476
Abstract
Acylcarnitines play an essential role in regulating the balance of intracellular sugar and lipid metabolism. They serve as carriers to transport activated long-chain fatty acids into mitochondria for β-oxidation as a major source of energy for cell activities. The liver is the most [...] Read more.
Acylcarnitines play an essential role in regulating the balance of intracellular sugar and lipid metabolism. They serve as carriers to transport activated long-chain fatty acids into mitochondria for β-oxidation as a major source of energy for cell activities. The liver is the most important organ for endogenous carnitine synthesis and metabolism. Hepatocellular carcinoma (HCC), a primary malignancy of the live with poor prognosis, may strongly influence the level of acylcarnitines. In this paper, the function, detection and alteration of acylcarnitine metabolism in HCC were briefly reviewed. An overview was provided to introduce the metabolic roles of acylcarnitines involved in fatty acid β-oxidation. Then different analytical platforms and methodologies were also briefly summarised. The relationship between HCC and acylcarnitine metabolism was described. Many of the studies reported that short, medium and long-chain acylcarnitines were altered in HCC patients. These findings presented current evidence in support of acylcarnitines as new candidate biomarkers for studies on the pathogenesis and development of HCC. Finally we discussed the challenges and perspectives of exploiting acylcarnitine metabolism and its related metabolic pathways as a target for HCC diagnosis and prognosis. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2018)
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27 pages, 2410 KiB  
Review
HR-MAS NMR Based Quantitative Metabolomics in Breast Cancer
by Mikheil Gogiashvili, Jessica Nowacki, Roland Hergenröder, Jan G. Hengstler, Jörg Lambert and Karolina Edlund
Metabolites 2019, 9(2), 19; https://doi.org/10.3390/metabo9020019 - 22 Jan 2019
Cited by 35 | Viewed by 6096
Abstract
High resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy is increasingly used for profiling of breast cancer tissue, delivering quantitative information for approximately 40 metabolites. One unique advantage of the method is that it can be used to analyse intact tissue, thereby [...] Read more.
High resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy is increasingly used for profiling of breast cancer tissue, delivering quantitative information for approximately 40 metabolites. One unique advantage of the method is that it can be used to analyse intact tissue, thereby requiring only minimal sample preparation. Importantly, since the method is non-destructive, it allows further investigations of the same specimen using for instance transcriptomics. Here, we discuss technical aspects critical for a successful analysis—including sample handling, measurement conditions, pulse sequences for one- and two dimensional analysis, and quantification methods—and summarize available studies, with a focus on significant associations of metabolite levels with clinically relevant parameters. Full article
(This article belongs to the Special Issue Cancer Metabolomics 2018)
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