Special Issue "Cancer Metabolomics"

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A special issue of Metabolites (ISSN 2218-1989).

Deadline for manuscript submissions: closed (31 March 2014)

Special Issue Editors

Guest Editor
Dr. Julian Griffin (Website)

Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK
Interests: diabetes; cancer; metabolomics
Guest Editor
Dr. Luigi Atzori

Department of Toxicology, Oncology Molecular Pathology Unit, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy
Interests: applications of metabolomics in biomedical field; Identification of disease markers

Special Issue Information

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).

Published Papers (10 papers)

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Research

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Open AccessArticle Stable Isotope Tracer Analysis in Isolated Mitochondria from Mammalian Systems
Metabolites 2014, 4(2), 166-183; doi:10.3390/metabo4020166
Received: 21 November 2013 / Revised: 26 February 2014 / Accepted: 24 March 2014 / Published: 10 April 2014
Cited by 3 | PDF Full-text (495 KB) | HTML Full-text | XML Full-text
Abstract
Mitochondria are a focal point in metabolism, given that they play fundamental roles in catabolic, as well as anabolic reactions. Alterations in mitochondrial functions are often studied in whole cells, and metabolomics experiments using 13C-labeled substrates, coupled with mass isotopomer distribution [...] Read more.
Mitochondria are a focal point in metabolism, given that they play fundamental roles in catabolic, as well as anabolic reactions. Alterations in mitochondrial functions are often studied in whole cells, and metabolomics experiments using 13C-labeled substrates, coupled with mass isotopomer distribution analyses, represent a powerful approach to study global changes in cellular metabolic activities. However, little is known regarding the assessment of metabolic activities in isolated mitochondria using this technology. Studies on isolated mitochondria permit the evaluation of whether changes in cellular metabolic activities are due to modifications in the intrinsic properties of the mitochondria. Here, we present a streamlined approach to accurately determine 13C, as well as 12C enrichments in isolated mitochondria from mammalian tissues or cultured cells by GC/MS. We demonstrate the relevance of this experimental approach by assessing the effects of drugs perturbing mitochondrial functions on the mass isotopomer enrichment of metabolic intermediates. Furthermore, we investigate 13C and 12C enrichments in mitochondria isolated from cancer cells given the emerging role of metabolic alterations in supporting tumor growth. This original method will provide a very sensitive tool to perform metabolomics studies on isolated mitochondria. Full article
(This article belongs to the Special Issue Cancer Metabolomics)
Open AccessArticle Glycerophosphoglycerol, Beta-Alanine, and Pantothenic Acid as Metabolic Companions of Glycolytic Activity and Cell Migration in Breast Cancer Cell Lines
Metabolites 2013, 3(4), 1084-1101; doi:10.3390/metabo3041084
Received: 20 August 2013 / Revised: 16 October 2013 / Accepted: 24 October 2013 / Published: 27 November 2013
Cited by 2 | PDF Full-text (903 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In cancer research, cell lines are used to explore the molecular basis of the disease as a substitute to tissue biopsies. Breast cancer in particular is a very heterogeneous type of cancer, and different subgroups of cell lines have been established according [...] Read more.
In cancer research, cell lines are used to explore the molecular basis of the disease as a substitute to tissue biopsies. Breast cancer in particular is a very heterogeneous type of cancer, and different subgroups of cell lines have been established according to their genomic profiles and tumor characteristics. We applied GCMS metabolite profiling to five selected breast cancer cell lines and found this heterogeneity reflected on the metabolite level as well. Metabolite profiles of MCF-7 cells belonging to the luminal gene cluster proved to be more different from those of the basal A cell line JIMT-1 and the basal B cell lines MDA-MB-231, MDA-MB-435, and MDA-MB-436 with only slight differences in the intracellular metabolite pattern. Lactate release into the cultivation medium as an indicator of glycolytic activity was correlated to the metabolite profiles and physiological characteristics of each cell line. In conclusion, pantothenic acid, beta-alanine and glycerophosphoglycerol appeared to be related to the glycolytic activity designated through high lactate release. Other physiological parameters coinciding with glycolytic activity were high glyoxalase 1 (Glo1) and lactate dehydrogenase (LDH) enzyme activity as well as cell migration as an additional important characteristic contributing to the aggressiveness of tumor cells. Metabolite profiles of the cell lines are comparatively discussed with respect to known biomarkers of cancer progression. Full article
(This article belongs to the Special Issue Cancer Metabolomics)
Figures

Open AccessArticle Global Metabolomics Reveals Urinary Biomarkers of Breast Cancer in a MCF-7 Xenograft Mouse Model
Metabolites 2013, 3(3), 658-672; doi:10.3390/metabo3030658
Received: 21 June 2013 / Revised: 2 August 2013 / Accepted: 2 August 2013 / Published: 7 August 2013
Cited by 2 | PDF Full-text (950 KB) | HTML Full-text | XML Full-text
Abstract
Global metabolomics analysis has the potential to uncover novel metabolic pathways that are differentially regulated during carcinogenesis, aiding in biomarker discovery for early diagnosis and remission monitoring. Metabolomics studies with human samples can be problematic due to high inter-individual variation; however xenografts [...] Read more.
Global metabolomics analysis has the potential to uncover novel metabolic pathways that are differentially regulated during carcinogenesis, aiding in biomarker discovery for early diagnosis and remission monitoring. Metabolomics studies with human samples can be problematic due to high inter-individual variation; however xenografts of human cancers in mice offer a well-controlled model system. Urine was collected from a xenograft mouse model of MCF-7 breast cancer and analyzed by mass spectrometry-based metabolomics to identify metabolites associated with cancer progression. Over 10 weeks, 24 h urine was collected weekly from control mice, mice dosed with estradiol cypionate (1 mg/mL), mice inoculated with MCF-7 cells (1 × 107) and estradiol cypionate (1 mg/mL), and mice dosed with MCF-7 cells (1 × 107) only (n = 10/group). Mice that received both estradiol cypionate and MCF-7 cells developed tumors from four weeks after inoculation. Five urinary metabolites were identified that were associated with breast cancer; enterolactone glucuronide, coumaric acid sulfate, capric acid glucuronide, an unknown metabolite, and a novel mammalian metabolite, “taurosebacic acid”. These metabolites revealed a correlation between tumor growth, fatty acid synthesis, and potential anti-proliferative effects of gut microbiota-metabolized food derivatives. These biomarkers may be of value for early diagnosis of cancer, monitoring of cancer therapeutics, and may also lead to future mechanistic studies. Full article
(This article belongs to the Special Issue Cancer Metabolomics)
Open AccessArticle Metabolic Profiling of Plasma from Benign and Malignant Pulmonary Nodules Patients Using Mass Spectrometry-Based Metabolomics
Metabolites 2013, 3(3), 539-551; doi:10.3390/metabo3030539
Received: 3 May 2013 / Revised: 7 June 2013 / Accepted: 24 June 2013 / Published: 4 July 2013
Cited by 3 | PDF Full-text (637 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Solitary pulmonary nodule (SPN or coin lesion) is a mass in the lung and can be commonly found in chest X-rays or computerized tomography (CT) scans. However, despite the advancement of imaging technologies, it is still difficult to distinguish malignant cancer from [...] Read more.
Solitary pulmonary nodule (SPN or coin lesion) is a mass in the lung and can be commonly found in chest X-rays or computerized tomography (CT) scans. However, despite the advancement of imaging technologies, it is still difficult to distinguish malignant cancer from benign SPNs. Here we investigated the metabolic profiling of patients with benign and malignant pulmonary nodules. A combination of gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) was used to profile the plasma metabolites in 17 patients with malignant SPNs, 15 patients with benign SPNs and 20 healthy controls. The metabolic profiles were assayed using OPLS-DA, and further analyzed to identify marker metabolites related to diseases. Both GC/MS- and LC/MS-derived models showed clear discriminations in metabolic profiles among three groups. It was found that 63 metabolites (12 from GC/MS, 51 from LC/MS) contributed to the differences. Of these, 48 metabolites showed same change trend in both malignant and benign SPNs as compared with healthy controls, indicating some common pathways including inflammation and oxidative injury shared by two diseases. In contrast, 14 metabolites constituted distinct profiles that differentiated malignant from benign SPNs, which might be a unique biochemical feature associated with lung cancer. Overall, our data suggested that integration of two highly sensitive and complementary metabolomics platforms could enable a comprehensive metabolic profiling and assist in discrimination malignant from benign SPNs. Full article
(This article belongs to the Special Issue Cancer Metabolomics)

Review

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Open AccessReview Application of Metabolomics in Drug Resistant Breast Cancer Research
Metabolites 2015, 5(1), 100-118; doi:10.3390/metabo5010100
Received: 7 February 2014 / Revised: 18 August 2014 / Accepted: 24 December 2014 / Published: 16 February 2015
Cited by 5 | PDF Full-text (617 KB) | HTML Full-text | XML Full-text
Abstract
The metabolic profiles of breast cancer cells are different from normal mammary epithelial cells. Breast cancer cells that gain resistance to therapeutic interventions can reprogram their endogenous metabolism in order to adapt and proliferate despite high oxidative stress and hypoxic conditions. Drug [...] Read more.
The metabolic profiles of breast cancer cells are different from normal mammary epithelial cells. Breast cancer cells that gain resistance to therapeutic interventions can reprogram their endogenous metabolism in order to adapt and proliferate despite high oxidative stress and hypoxic conditions. Drug resistance in breast cancer, regardless of subgroups, is a major clinical setback. Although recent advances in genomics and proteomics research has given us a glimpse into the heterogeneity that exists even within subgroups, the ability to precisely predict a tumor’s response to therapy remains elusive. Metabolomics as a quantitative, high through put technology offers promise towards devising new strategies to establish predictive, diagnostic and prognostic markers of breast cancer. Along with other “omics” technologies that include genomics, transcriptomics, and proteomics, metabolomics fits into the puzzle of a comprehensive systems biology approach to understand drug resistance in breast cancer. In this review, we highlight the challenges facing successful therapeutic treatment of breast cancer and the innovative approaches that metabolomics offers to better understand drug resistance in cancer. Full article
(This article belongs to the Special Issue Cancer Metabolomics)
Open AccessReview Applying Metabolomics to Understand the Aggressive Phenotype and Identify Novel Therapeutic Targets in Glioblastoma
Metabolites 2014, 4(3), 740-750; doi:10.3390/metabo4030740
Received: 17 March 2014 / Revised: 20 August 2014 / Accepted: 21 August 2014 / Published: 27 August 2014
Cited by 2 | PDF Full-text (199 KB) | HTML Full-text | XML Full-text
Abstract
Glioblastoma continues to be an invariably fatal malignancy. The established approach for understanding the biology of these aggressive tumors in an effort to identify novel molecular targets has largely been genotype-based. Unfortunately, clinical gains offered by this level of understanding have been [...] Read more.
Glioblastoma continues to be an invariably fatal malignancy. The established approach for understanding the biology of these aggressive tumors in an effort to identify novel molecular targets has largely been genotype-based. Unfortunately, clinical gains offered by this level of understanding have been limited, largely based on the complex nature of signaling networks associated with tumorigenesis and the inability to delineate the key “functional” signaling pathways actually driving growth in an individual tumor. Metabolomics is the global quantitative assessment of endogenous metabolites within a biological system, taking into account genetic regulation, altered kinetic activity of enzymes, and changes in metabolic reactions. Thus, compared to genomics and proteomics, metabolomics reflects changes in phenotype and therefore function. In this review, we highlight some of the key advancements that have been made in applying metabolomics to understand the aggressive phenotype of glioblastoma. Collectively, these studies have provided a previously unrecognized window into the underlying biology of these tumors. Current and future efforts are designed to determine how this technology may be applied to improve diagnosis and predict the aggressiveness of glioblastoma, and more importantly, identify novel, therapeutic strategies designed to improve clinical outcomes. Full article
(This article belongs to the Special Issue Cancer Metabolomics)
Open AccessReview Metformin: On Ongoing Journey across Diabetes, Cancer Therapy and Prevention
Metabolites 2013, 3(4), 1051-1075; doi:10.3390/metabo3041051
Received: 10 July 2013 / Revised: 27 September 2013 / Accepted: 31 October 2013 / Published: 7 November 2013
Cited by 6 | PDF Full-text (320 KB) | HTML Full-text | XML Full-text
Abstract
Cancer metabolism is the focus of intense research, which witnesses its key role in human tumors. Diabetic patients treated with metformin exhibit a reduced incidence of cancer and cancer-related mortality. This highlights the possibility that the tackling of metabolic alterations might also [...] Read more.
Cancer metabolism is the focus of intense research, which witnesses its key role in human tumors. Diabetic patients treated with metformin exhibit a reduced incidence of cancer and cancer-related mortality. This highlights the possibility that the tackling of metabolic alterations might also hold promising value for treating cancer patients. Here, we review the emerging role of metformin as a paradigmatic example of an old drug used worldwide to treat patients with type II diabetes which to date is gaining strong in vitro and in vivo anticancer activities to be included in clinical trials. Metformin is also becoming the focus of intense basic and clinical research on chemoprevention, thus suggesting that metabolic alteration is an early lesion along cancer transformation. Metabolic reprogramming might be a very efficient prevention strategy with a profound impact on public health worldwide. Full article
(This article belongs to the Special Issue Cancer Metabolomics)
Open AccessReview The Complex Role of Branched Chain Amino Acids in Diabetes and Cancer
Metabolites 2013, 3(4), 931-945; doi:10.3390/metabo3040931
Received: 31 July 2013 / Revised: 3 September 2013 / Accepted: 8 October 2013 / Published: 14 October 2013
Cited by 18 | PDF Full-text (253 KB) | HTML Full-text | XML Full-text
Abstract
The obesity and diabetes epidemics are continuing to spread across the globe. There is increasing evidence that diabetes leads to a significantly higher risk for certain types of cancer. Both diabetes and cancer are characterized by severe metabolic perturbations and the branched [...] Read more.
The obesity and diabetes epidemics are continuing to spread across the globe. There is increasing evidence that diabetes leads to a significantly higher risk for certain types of cancer. Both diabetes and cancer are characterized by severe metabolic perturbations and the branched chain amino acids (BCAAs) appear to play a significant role in both of these diseases. These essential amino acids participate in a wide variety of metabolic pathways, but it is now recognized that they are also critical regulators of a number of cell signaling pathways. An elevation in branched chain amino acids has recently been shown to be significantly correlated with insulin resistance and the future development of diabetes. In cancer, the normal demands for BCAAs are complicated by the conflicting needs of the tumor and the host. The severe muscle wasting syndrome experience by many cancer patients, known as cachexia, has motivated the use of BCAA supplementation. The desired improvement in muscle mass must be balanced by the need to avoid providing materials for tumor proliferation. A better understanding of the complex functions of BCAAs could lead to their use as biomarkers of the progression of certain cancers in diabetic patients. Full article
(This article belongs to the Special Issue Cancer Metabolomics)
Figures

Open AccessReview A Review of Applications of Metabolomics in Cancer
Metabolites 2013, 3(3), 552-574; doi:10.3390/metabo3030552
Received: 24 April 2013 / Revised: 17 May 2013 / Accepted: 24 June 2013 / Published: 5 July 2013
Cited by 26 | PDF Full-text (262 KB) | HTML Full-text | XML Full-text
Abstract
Cancer is a devastating disease that alters the metabolism of a cell and the surrounding milieu. Metabolomics is a growing and powerful technology capable of detecting hundreds to thousands of metabolites in tissues and biofluids. The recent advances in metabolomics technologies have [...] Read more.
Cancer is a devastating disease that alters the metabolism of a cell and the surrounding milieu. Metabolomics is a growing and powerful technology capable of detecting hundreds to thousands of metabolites in tissues and biofluids. The recent advances in metabolomics technologies have enabled a deeper investigation into the metabolism of cancer and a better understanding of how cancer cells use glycolysis, known as the “Warburg effect,” advantageously to produce the amino acids, nucleotides and lipids necessary for tumor proliferation and vascularization. Currently, metabolomics research is being used to discover diagnostic cancer biomarkers in the clinic, to better understand its complex heterogeneous nature, to discover pathways involved in cancer that could be used for new targets and to monitor metabolic biomarkers during therapeutic intervention. These metabolomics approaches may also provide clues to personalized cancer treatments by providing useful information to the clinician about the cancer patient’s response to medical interventions. Full article
(This article belongs to the Special Issue Cancer Metabolomics)

Other

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Open AccessBrief Report The Succinated Proteome of FH-Mutant Tumours
Metabolites 2014, 4(3), 640-654; doi:10.3390/metabo4030640
Received: 16 May 2014 / Revised: 21 July 2014 / Accepted: 24 July 2014 / Published: 7 August 2014
Cited by 5 | PDF Full-text (1641 KB) | HTML Full-text | XML Full-text
Abstract
Inherited mutations in the Krebs cycle enzyme fumarate hydratase (FH) predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). Loss of FH activity in HLRCC tumours causes accumulation of the Krebs cycle intermediate fumarate to high levels, which may act as an [...] Read more.
Inherited mutations in the Krebs cycle enzyme fumarate hydratase (FH) predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). Loss of FH activity in HLRCC tumours causes accumulation of the Krebs cycle intermediate fumarate to high levels, which may act as an oncometabolite through various, but not necessarily mutually exclusive, mechanisms. One such mechanism, succination, is an irreversible non-enzymatic modification of cysteine residues by fumarate, to form S-(2-succino)cysteine (2SC). Previous studies have demonstrated that succination of proteins including glyceraldehyde 3-phosphate dehydrogenase (GAPDH), kelch-like ECH-associated protein 1 (KEAP1) and mitochondrial aconitase (ACO2) can have profound effects on cellular metabolism. Furthermore, immunostaining for 2SC is a sensitive and specific biomarker for HLRCC tumours. Here, we performed a proteomic screen on an FH-mutant tumour and two HLRCC-derived cancer cell lines and identified 60 proteins where one or more cysteine residues were succinated; 10 of which were succinated at cysteine residues either predicted, or experimentally proven, to be functionally significant. Bioinformatic enrichment analyses identified most succinated targets to be involved in redox signaling. To our knowledge, this is the first proteomic-based succination screen performed in human tumours and cancer-derived cells and has identified novel 2SC targets that may be relevant to the pathogenesis of HLRCC. Full article
(This article belongs to the Special Issue Cancer Metabolomics)

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