DOCSLIB.ORG

Study of Early Stage Non-Small-Cell Lung Cancer Using Orbitrap-Based Global Serum Metabolomics

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Study of Early Stage Non-Small-Cell Lung Cancer Using Orbitrap-Based Global Serum Metabolomics J Cancer Res Clin Oncol DOI 10.1007/s00432-017-2347-0 ORIGINAL ARTICLE – CANCER RESEARCH Study of early stage non-small-cell lung cancer using Orbitrap- based global serum metabolomics Agnieszka Klupczynska1 · Paweł Dereziński1 · Timothy J. Garrett2 · Vanessa Y. Rubio2 · Wojciech Dyszkiewicz3 · Mariusz Kasprzyk3 · Zenon J. Kokot1 Received: 10 November 2016 / Accepted: 18 January 2017 © The Author(s) 2017. This article is published with open access at Springerlink.com Abstract a number of NSCLC biomarker candidates which belong Purpose The aim of the project was to apply ultra-high- to such compound classes as acylcarnitines, organic acids, performance liquid chromatography–quadrupole-Orbitrap- and amino acids. Multivariate ROC curve built using 12 high-resolution mass spectrometry for serum metabolite identified metabolites was characterized by AUC = 0.836 profiling of non-small-cell lung cancer (NSCLC). This (0.722–0.946). There were no significant differences in the Orbitrap-based methodology has been applied for a study serum metabolite profiles between two most common his- of NSCLC potential markers for the first time. tological types of lung cancer—adenocarcinoma and squa- Methods After extraction using protein precipita- mous cell carcinoma. tion, sera were separated on the ACE Excel 2 C18-PFP Conclusions Through identification of novel potential (100 × 2.1 mm, 2.0 µm) column using gradient elution and tumor markers, Orbitrap-based global metabolic profiling analyzed within the range of 70–1000 m/z. Only patients is a useful strategy in cancer research. Our study can accel- with early stage disease (stages IA–IIB) were included in erate development of new diagnostic and therapeutic strate- the study, providing opportunity to find biomarkers for gies in NSCLC. The metabolites involved in discrimination early lung cancer detection. The resulting metabolite pro- between NSCLC patients and the control subjects should files were subjected to univariate and multivariate statisti- be further explored using a targeted approach. cal tests. Results 36 features were found significantly changed Keywords Lung cancer · Global metabolomics · between NSCLC group and controls after FDR adjustment Metabolite profiling · Mass spectrometry · Orbitrap and 19 were identified using various metabolite databases (in-house library, HMDB, mzCloud). The study revealed Introduction Electronic supplementary material The online version of this article (doi:10.1007/s00432-017-2347-0) contains supplementary Recently, the growing trend of metabolomic studies of can- material, which is available to authorized users. cer has been observed. It is well known that cancer cells exhibit an altered metabolism and increased energy require- * Zenon J. Kokot [email protected] ments compared to normal cells. However, the tumor metabolome has not yet been fully explained (Aboud and 1 Department of Inorganic and Analytical Chemistry, Poznan Weiss 2013). In contrast to normal cells, which utilize oxi- University of Medical Sciences, Grunwaldzka 6 Street, dative phosphorylation for energy production, cancer cells 60-780 Poznan, Poland 2 gain energy from glycolysis occurring even in the presence Department of Pathology, Immunology and Laboratory of oxygen. This phenomenon is called the Warburg effect Medicine, College of Medicine, University of Florida, 1395 Center Drive, Gainesville, FL 32610, USA (Vander Heiden et al. 2009). Another distinctive trait of cancer cell metabolism is the use of glutamine as a main 3 Department of Thoracic Surgery, Poznan University of Medical Sciences, Szamarzewskiego 62 Street, source of energy (Reitzer et al. 1979; DeBerardinis et al. 60-569 Poznan, Poland 2008). The characteristic metabolic alterations occurring Vol.:(0123456789)1 3 J Cancer Res Clin Oncol in tumors might result in changed levels of some metabo- are still several gaps and inconsistencies in the knowledge lites in tissues and body fluids. Human biological fluids are about the serum metabolome of lung cancer patients. commonly recognized as vehicles for the transmission of Only detection of early metabolic alterations can lead markers of many human disorders and thus the metabolite to early lung cancer diagnosis. Therefore, it is of particu- profiling of different body fluids is a promising strategy in lar interest to study the utility of cancer-related metabolic cancer research. There is a multitude of potential applica- changes occurring at the beginning of the disease. Many of tions of metabolomics in oncology, including early and the metabolomic studies included late-stage cancer cases accurate diagnosis, estimation of treatment efficacy, and (Hori et al. 2011; Fahrmann et al. 2015; Miyamoto et al. development of novel anti-cancer therapies (Spratlin et al. 2015). Therefore, the putative biomarker metabolites iden- 2009). tified in those studies would likely fail a further valida- Application of high-throughput and sensitive analyti- tion step for early detection of cancer. It should be noted cal techniques that are used in metabolomics makes them that by including advanced stage patients in the research, powerful tools in the field of oncology and aids understand- the obtained results could be overoptimistic. Moreover, ing what is happening in cancer cells. Given the complex there is a risk, especially in the case of amino acids, that nature of cancer, global metabolomic profiling offers the the observed abnormalities are influenced by nutritional unique opportunity of broadening the knowledge on the deficiencies and accompanying weight loss experienced tumor metabolome. In particular, there is an increasing by many patients with advanced lung cancer (del Ferraro interest in the study of metabolic changes related to lung et al. 2012). The application of metabolomic research in cancer over the last few years (Hori et al. 2011; Chen et al. the discovery phase for new cancer biomarkers is indisput- 2014; Deja et al. 2014; Puchades-Carrasco et al. 2016). able; however, the selection of representative samples has a Lung cancer constitutes one of the greatest challenges major impact on any conclusions drawn from the research. in contemporary oncology because of difficulties in early The aim of the study was to apply an Orbitrap-based detection resulting in lung cancer as a leading cause of global metabolomic approach to the analysis of serum of cancer death for many years (Subramaniam et al. 2013). patients with non-small-cell lung cancer (NSCLC). To Blood metabolite profiling of lung cancer includes the our knowledge, this is the first study which presents the application of such analytical techniques as gas chroma- application of ultra-high-performance liquid chromatogra- tography–mass spectrometry (Hori et al. 2011; Musharraf phy–quadrupole-Orbitrap-high-resolution mass spectrom- et al. 2015; Fahrmann et al. 2015), ultra-high-performance etry (UHPLC-Q-Orbitrap-HRMS) for searching NSCLC liquid chromatography–linear ion trap-mass spectrometry potential markers. Until now, Orbitrap-based profiling has (Mazzone et al. 2016), high-performance liquid chromatog- only been used to compare two metabolomes (plasma and raphy–quadrupole-time-of-flight-mass spectrometry (Chen serum) of small-cell lung cancer (SCLC) patients undergo- et al. 2014; Li et al. 2014), and nuclear magnetic resonance ing treatment with standard chemotherapy (Wedge et al. (Deja et al. 2014; Puchades-Carrasco et al. 2016). In the 2011) and to characterize KRAS mutants in NSCLC cells above-mentioned studies, changes in many distinct groups (Brunelli et al. 2014). The current study provided new data of metabolites were reported, such as amino acids, carbohy- on metabolites, which could translate to the improvement drates, organic acids, fatty acids, and nucleotides. It should of lung cancer diagnosis and treatment. The study involved be noted that the results obtained in the previously pub- serum analysis of patients with newly diagnosed NSCLC lished metabolomic research were not always in agreement prior to initiation of a therapy and a matched control group. with each other. One of the discrepancies exists regarding Only patients with early stage disease (stage IA–IIB) were glutamate which was found elevated in blood of lung can- included to the study, representing an opportunity to define cer patients by Fahrmann et al. (2015) and Puchdes-Car- biomarkers for early lung cancer detection. rasco et al. (2016), whereas Hori et al. (2011) reported a decreased level. Another discrepancy is in the lactic acid level. According to Hori et al. (2011) and Musharraf et al. Methodology (2015), higher level of lactic acid occurred in the plasma of patients with lung cancer, whereas Chen et al. (2014) Reagents and materials observed its reduction in sera from lung cancer group as compared with controls. The possible reasons of the above- LC/MS grade acetonitrile, 0.1% formic acid in water, meth- mentioned discrepancies can be associated with differences anol, and acetone were purchased from Fischer Scientific in analytical methodologies, sample handling, or clinical Co. (Pittsburgh, PA, USA). Isotopically labeled stand- characteristics of patients. Therefore, it can be concluded ards: creatine-D3, L-leucine-D10, L-tryptophan-2,3,3-D3, that despite efforts made by many research groups, there and caffeine-D3 were obtained from CDN Isotopes Inc. 1 3 J Cancer Res Clin Oncol (Pointe-Claire, Quebec, Canada). Mixture of amino acids Table 1 Characteristics of the study participants was purchased from Sigma-Aldrich (St. Louis, MO, USA). Parameter Non-small-cell lung Control group cancer Study population N Total 50 25 The project was approved by the ethics committee at the Male 28 (56.0%) 14 (56.0%) Poznan University of Medical Sciences (Decision No. Female 22 (44.0%) 11 (44.0%) 200/13). All participants provided a written informed con- Age, year sent for inclusion to the study. Fifty lung cancer patients Mean 65 64 were recruited in the Department of Thoracic Surgery, Range 53–86 50–78 Poznan University of Medical Sciences. NSCLC diagno- BMI, kg/m2 sis was conducted by the histopathological examination of Mean 26.5 25.8 tissue samples. Patients with other tumors were excluded Range 17.6–33.9 21.1–34.6 from the study.
Load more

Recommended publications
  • Interplay Between Epigenetics and Metabolism in Oncogenesis: Mechanisms and Therapeutic Approaches
    OPEN Oncogene (2017) 36, 3359–3374 www.nature.com/onc REVIEW Interplay between epigenetics and metabolism in oncogenesis: mechanisms and therapeutic approaches CC Wong1, Y Qian2,3 and J Yu1 Epigenetic and metabolic alterations in cancer cells are highly intertwined. Oncogene-driven metabolic rewiring modifies the epigenetic landscape via modulating the activities of DNA and histone modification enzymes at the metabolite level. Conversely, epigenetic mechanisms regulate the expression of metabolic genes, thereby altering the metabolome. Epigenetic-metabolomic interplay has a critical role in tumourigenesis by coordinately sustaining cell proliferation, metastasis and pluripotency. Understanding the link between epigenetics and metabolism could unravel novel molecular targets, whose intervention may lead to improvements in cancer treatment. In this review, we summarized the recent discoveries linking epigenetics and metabolism and their underlying roles in tumorigenesis; and highlighted the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these abnormalities in cancer. Oncogene (2017) 36, 3359–3374; doi:10.1038/onc.2016.485; published online 16 January 2017 INTRODUCTION metabolic genes have also been identified as driver genes It has been appreciated since the early days of cancer research mutated in some cancers, such as isocitrate dehydrogenase 1 16 17 that the metabolic profiles of tumor cells differ significantly from and 2 (IDH1/2) in gliomas and acute myeloid leukemia (AML), 18 normal cells. Cancer cells have high metabolic demands and they succinate dehydrogenase (SDH) in paragangliomas and fuma- utilize nutrients with an altered metabolic program to support rate hydratase (FH) in hereditary leiomyomatosis and renal cell 19 their high proliferative rates and adapt to the hostile tumor cancer (HLRCC).
    [Show full text]
  • Multivariate Profiling of Metabolites in Human Disease
    Multivariate Profiling of Metabolites in Human Disease Method evaluation and application to prostate cancer Elin Thysell Department of Chemistry Umeå University, Sweden 2012 Copyright © Elin Thysell ISBN: 978-91-7459-344-0 Front cover picture by Petrus Sjövik Johansson Elektronisk version tillgänglig på http://umu.diva-portal.org/ Tryck/Printed by: VMC-KBC Umeå Umeå, Sweden 2012 To my family i ii Abstract There is an ever increasing need of new technologies for identification of molecular markers for early diagnosis of fatal diseases to allow efficient treatment. In addition, there is great value in finding patterns of metabolites, proteins or genes altered in relation to specific disease conditions to gain a deeper understanding of the underlying mechanisms of disease development. If successful, scientific achievements in this field could apart from early diagnosis lead to development of new drugs, treatments or preventions for many serious diseases. Metabolites are low molecular weight compounds involved in the chemical reactions taking place in the cells of living organisms to uphold life, i.e. metabolism. The research field of metabolomics investigates the relationship between metabolite alterations and biochemical mechanisms, e.g. disease processes. To understand these associations hundreds of metabolites present in a sample are quantified using sensitive bioanalytical techniques. In this way a unique chemical fingerprint is obtained for each sample, providing an instant picture of the current state of the studied system. This fingerprint or picture can then be utilized for the discovery of biomarkers or biomarker patterns of biological and clinical relevance. In this thesis the focus is set on evaluation and application of strategies for studying metabolic alterations in human tissues associated with disease.
    [Show full text]
  • Tumor Metabolome: Therapeutic Opportunities Targeting Cancer Metabolic Reprogramming
    cancers Editorial Tumor Metabolome: Therapeutic Opportunities Targeting Cancer Metabolic Reprogramming Javier Márquez 1,2,* and José M. Matés 1,2,* 1 Departamento de Biología Molecular y Bioquímica, Canceromics Lab, Universidad de Málaga, 29071 Málaga, Spain 2 Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain * Correspondence: [email protected] (J.M.); [email protected] (J.M.M.); Tel.: +34-95-213-2024 (J.M.); +34-95-213-3430 (J.M.M.) The study of cancer metabolism is regaining center stage and becoming a hot topic in tumor biology and clinical research, after a period where such kind of experimental ap- proaches were somehow forgotten or disregarded in favor of powerful functional genomic and proteomic studies. Paradoxically, this renewed interest has been largely provoked by sound results from canceromics (cancer genomic, proteomic, and metabolomic) studies which are now identifying key drivers of cancer progression, metastasis and resistance to therapy, as well as revealing novel molecular mechanisms underlying cell proliferation in tumors. Thus, sound canceromics results are renewing the interest into metabolic studies which are recovering their original high-profile status in cancer research. Cancer cells have metabolic requirements that separate them from normal cells and render them vulnerable to drugs that target these processes. The altered metabolism exhibited by most tumor cells is a hallmark of cancer. Pioneer works studying differential metabolic traits of cancer cells firstly classified tumors as glucose and nitrogen traps, thus reflecting the ability of tumors to avidly consume both nutrients. In the last years, metabolic studies using omics technologies are more precisely unveiling the tumor metabolome and Citation: Márquez, J.; Matés, J.M.
    [Show full text]
  • Clinical Applications of Metabolomics in Oncology: a Review Jennifer L
    Review Clinical Applications of Metabolomics in Oncology: A Review Jennifer L. Spratlin,1Natalie J. Serkova,2 and S. Gail Eckhardt1 Abstract Metabolomics, an omic science in systems biology, is the global quantitative assessment of endogenous metabolites within a biological system. Either individually or grouped as a metabo- lomic profile, detection of metabolites is carried out in cells, tissues, or biofluids by either nuclear magnetic resonance spectroscopy or mass spectrometry.There is potential for the metabolome to have a multitude of uses in oncology, including the early detection and diagnosis of cancer and as both a predictive and pharmacodynamic marker of drug effect. Despite this, there is lack of knowledge in the oncology community regarding metabolomics and confusion about its metho- dologic processes, technical challenges, and clinical applications. Metabolomics, when used as a translational research tool, can provide a link between the laboratory and clinic, particularly because metabolic and molecular imaging technologies, such as positron emission tomography and magnetic resonance spectroscopic imaging, enable the discrimination of metabolic markers noninvasively in vivo. Here, we review the current and potential applications of metabolomics, focusing on its use as a biomarker for cancer diagnosis, prognosis, and therapeutic evaluation. which focuses on a particular segment of the metabolome by History and Definitions analyzing only a few selected metabolites that comprise a The omic sciences of systems biology (Fig. 1), including specific biochemical pathway (7). genomics, transcriptomics, proteomics, and metabolomics, Metabolomics allows for a global assessment of a cellular have been in existence for decades, whereas much attention state within the context of the immediate environment, taking has been focused on their development and application in the into account genetic regulation, altered kinetic activity of last several years.
    [Show full text]
  • Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment
    REVIEW published: 08 March 2017 doi: 10.3389/fimmu.2017.00248 Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment Kathrin Renner1,2, Katrin Singer1, Gudrun E. Koehl3, Edward K. Geissler3, Katrin Peter1, Peter J. Siska1 and Marina Kreutz1,2* 1 Internal Medicine III, University Hospital Regensburg, Regensburg, Germany, 2 Regensburg Center for Interventional Immunology, Regensburg, Germany, 3 Department of Surgery, University Hospital Regensburg, Regensburg, Germany Cytotoxic T lymphocytes and NK cells play an important role in eliminating malignant tumor cells and the number and activity of tumor-infiltrating T cells represent a good marker for tumor prognosis. Based on these findings, immunotherapy, e.g., checkpoint blockade, has received considerable attention during the last couple of years. However, for the majority of patients, immune control of their tumors is gray theory as malignant cells use effective mechanisms to outsmart the immune system. Increasing evidence suggests that changes in tumor metabolism not only ensure an effective energy supply and generation of building blocks for tumor growth but also contribute to inhibition of the antitumor response. Immunosuppression in the tumor microenvironment is often based on the mutual metabolic requirements of immune cells and tumor cells. Cytotoxic T and Edited by: NK cell activation leads to an increased demand for glucose and amino acids, a well- Christoph Hess, University of Basel, Switzerland known feature shown by tumor cells. These close metabolic interdependencies result in Reviewed by: metabolic competition, limiting the proliferation, and effector functions of tumor-specific Markus Munder, immune cells. Moreover, not only nutrient restriction but also tumor-driven shifts in University of Mainz, Germany metabolite abundance and accumulation of metabolic waste products (e.g., lactate) lead Alfred Zippelius, University of Basel, Switzerland to local immunosuppression, thereby facilitating tumor progression and metastasis.
    [Show full text]
  • Altered Controls Transforming Normal Metabolism Into Carcinogenic
    Journal of Cancer Prevention & Current Research Mini Review Open Access Altered controls transforming normal metabolism into carcinogenic Abstract Volume 7 Issue 2 - 2017 We show how normal metabolism can be transformed into a carcinogenic metabolism Maurice Israël in various conditions affecting its controls. A chronic GABA deficiency of the endocrine CNRS, France pancreas that perturbs the regulated secretion of insulin and glucagon will for example, change in a different way the metabolism of stem cells and differentiated cells, leading Correspondence: Maurice Israel, CNRS, 2 Av. Aristide Briand to a metabolic rewiring process that is advantageous for stem cells; such a rewiring is 91440, Bures sur Yvette, France, Email typical for cancer. We also discuss the role of PKC in normal metabolism and cancer, giving indications for correcting the carcinogenic metabolic rewiring process. Received: November 28, 2016 | Published: January 17, 2017 Keywords: cancer metabolism, GABA, glucagon, insulin, PKC, stem cells, anti-cancer drugs Abbreviations: PKA, protein kinase a; PKB, protein glycogen stores is elicited by the phosphorylation and activation kinase b; PKC, protein kinase c; IGF, insulin like growth factor; of phosphorylase a, while the synthesis of glycogen by glycogen MAPK, mitogen-activated protein kinase pathway; PI3 Kinase, synthase is blocked by GSK phosphorylation. As for lipolysis, phosphatidylinositide 3-kinase pathway ; PK, pyruvate kinase; PDH, hormone sensitive lipase (HSL) is activated by phosphorylation, pyruvate dehydrogenase; HSL, hormone sensitive lipase; PEPCK, fatty acid are produced, transported by the canityl transporter in liver phosphoenolpyruvate carboxykinase; ACC, acetyl-coa, carboxylase; mitochondria and form ketone bodies by beta-oxidation. Ketone GSK, glycogen synthase kinase 3; AMP Kin, amp-activated kinase; bodies may then provide other tissues with acetyl- CoA.
    [Show full text]
  • Pyruvate Kinase Type M2: a Crossroad in the Tumor Metabolome
    Downloaded from British Journal of Nutrition (2002), 87, Suppl. 1, S23–S29 DOI: 10.1079/BJN2001454 q The Authors, 2002 https://www.cambridge.org/core Pyruvate kinase type M2: a crossroad in the tumor metabolome S. Mazurek1, H. Grimm2, C. B. Boschek3, P. Vaupel4 and E. Eigenbrodt1* 1 Institute for Biochemistry & Endocrinology, Veterinary Faculty, University of Giessen, Frankfurter Strasse 100, 35392 . IP address: Giessen, Germany 2Centre of Surgery, Medical Faculty, University of Giessen, Klinikstrasse 29, 35392 Giessen, Germany 3 Institute for Medical Virology, Medical Faculty, University of Giessen, Frankfurter Strasse 107, 35392 Giessen, Germany 170.106.35.76 4Institute of Physiology and Pathophysiology, Medical Faculty, University of Mainz, Duesbergweg 6, 55099 Mainz, Germany , on 01 Oct 2021 at 23:28:20 Cell proliferation is a process that consumes large amounts of energy. A reduction in the nutrient supply can lead to cell death by ATP depletion, if cell proliferation is not limited. A key sensor for this regulation is the glycolytic enzyme pyruvate kinase, which determines whether glucose carbons are channelled to synthetic processes or used for glycolytic energy production. In unicellular organisms pyruvate kinase is regulated by ATP, ADP and AMP, by ribose 5-P, the precursor of the nucleic acid synthesis, and by the glycolytic intermediate , subject to the Cambridge Core terms of use, available at fructose 1,6-P2 (FBP), thereby adapting cell proliferation to nutrient supply. The mammalian pyruvate kinase isoenzyme type M2 (M2-PK) displays the same kinetic properties as the pyruvate kinase enzyme from unicellular organisms. The mammalian M2-PK isoenzyme can switch between a less active dimeric form and a highly active tetrameric form which regulates the channeling of glucose carbons either to synthetic processes (dimeric form) or to glycolytic energy production (tetrameric form).
    [Show full text]
  • A Global View of the Biochemical Pathways Involved in the Regulation of the Metabolism of Cancer Cells
    Biochimica et Biophysica Acta 1826 (2012) 423–433 Contents lists available at SciVerse ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbacan Review A global view of the biochemical pathways involved in the regulation of the metabolism of cancer cells Philippe Icard a,b,⁎, Hubert Lincet a a Unité “Biologie et Thérapies Innovantes des Cancers Localement Agressifs” (BioTICLA EA 4656), IFR 146 ICORE, Université of Caen Basse-Normandie, and Centre de Lutte Contre le Cancer François Baclesse, Avenue du Général Harris, BP5026, 14076 Caen Cedex 05, France b University Hospital, Caen, France article info abstract Article history: Cancer cells increase glucose uptake and reject lactic acid even in the presence of oxygen (Warburg effect). This Received 1 June 2012 metabolism reorients glucose towards the pentose phosphate pathway for ribose synthesis and consumes great Received in revised form 9 July 2012 amounts of glutamine to sustain nucleotide and fatty acid synthesis. Oxygenated and hypoxic cells cooperate and Accepted 10 July 2012 use their environment in a manner that promotes their development. Coenzymes (NAD+, NADPH,H+)are Available online 25 July 2012 required in abundance, whereas continuous consumption of ATP and citrate precludes the negative feedback of these molecules on glycolysis, a regulation supporting the Pasteur effect. Understanding the metabolism of Keywords: Energetic metabolism cancer cells may help to develop new anti-cancer treatments. Biochemical pathways © 2012 Elsevier B.V. All rights reserved. Citrate Phosphofructokinase Contents 1. Introduction .............................................................. 424 2. The metabolism of cancer cells: The importance of the Warburg effect and loss of the Pasteur effect .................... 424 2.1.
    [Show full text]
  • Metabolic Landscapes in Sarcomas Richard Miallot1*, Franck Galland1, Virginie Millet1, Jean‑Yves Blay2 and Philippe Naquet1*
    Miallot et al. J Hematol Oncol (2021) 14:114 https://doi.org/10.1186/s13045-021-01125-y REVIEW Open Access Metabolic landscapes in sarcomas Richard Miallot1*, Franck Galland1, Virginie Millet1, Jean‑Yves Blay2 and Philippe Naquet1* Abstract Metabolic rewiring ofers novel therapeutic opportunities in cancer. Until recently, there was scant information regard‑ ing soft tissue sarcomas, due to their heterogeneous tissue origin, histological defnition and underlying genetic his‑ tory. Novel large‑scale genomic and metabolomics approaches are now helping stratify their physiopathology. In this review, we show how various genetic alterations skew activation pathways and orient metabolic rewiring in sarcomas. We provide an update on the contribution of newly described mechanisms of metabolic regulation. We underscore mechanisms that are relevant to sarcomagenesis or shared with other cancers. We then discuss how diverse meta‑ bolic landscapes condition the tumor microenvironment, anti‑sarcoma immune responses and prognosis. Finally, we review current attempts to control sarcoma growth using metabolite‑targeting drugs. Keywords: Sarcoma, Metabolism, Microenvironment, Metabolomics, Transcriptomics, Metabolite‑targeted therapies Background improving sarcoma typing and treatment requires the Sarcomas encompass a wide variety of tumors, with more use of large-scale “omics” tools to identify the oncogenic than 170 subtypes, according to the last WHO classif- drivers, often resulting from multiple genetic alterations cation. Tey originate from the neoplastic transforma- in adult STS. Tese can include translocations, mutations tion of mesenchymal cells in connective tissues [1, 2]: or amplifcations/deletions that cripple major growth and 87% arise from soft tissue and 13% from bone [3, 4]. Soft diferentiation pathways [8–12]. tissue sarcoma (STS) presents as an indolent or aggres- Given the limits of current treatments, exploiting drugs sive disease, often only diagnosed at an advanced and/or targeting metabolic pathways may pave the way to efec- metastatic stages.
    [Show full text]
  • Correlation of Metabolic Profiles of Plasma and Cerebrospinal Fluid Of
    H OH metabolites OH Article Correlation of Metabolic Profiles of Plasma and Cerebrospinal Fluid of High-Grade Glioma Patients Artem D. Rogachev 1,2,* , Nikolay A. Alemasov 3 , Vladimir A. Ivanisenko 3 , Nikita V. Ivanisenko 3, Evgeniy V. Gaisler 1, Olga S. Oleshko 1 , Sergey V. Cheresiz 1 , Sergey V. Mishinov 4 , Vyacheslav V. Stupak 4 and Andrey G. Pokrovsky 1 1 V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, Pirogov str., 2, 630090 Novosibirsk, Russia; [email protected] (E.V.G.); [email protected] (O.S.O.); [email protected] (S.V.C.); [email protected] (A.G.P.) 2 N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, acad. Lavrentiev ave., 9, 630090 Novosibirsk, Russia 3 Institute of Cytology and Genetics of Siberian Branch of Russian Academy of Sciences, acad. Lavrentiev ave., 10, 630090 Novosibirsk, Russia; [email protected] (N.A.A.); [email protected] (V.A.I.); [email protected] (N.V.I.) 4 FSBI “Novosibirsk Research Institute of Traumatology and Orthopedics Named after Ya. L. Tsiviyan”, Frunze str., 17, 630091 Novosibirsk, Russia; [email protected] (S.V.M.); [email protected] (V.V.S.) * Correspondence: [email protected]; Tel.: +7-(383)-330-97-47 Abstract: This work compares the metabolic profiles of plasma and the cerebrospinal fluid (CSF) of the patients with high-grade (III and IV) gliomas and the conditionally healthy controls using the Citation: Rogachev, A.D.; Alemasov, wide-range targeted screening of low molecular metabolites by HPLC-MS/MS. The obtained data N.A.; Ivanisenko, V.A.; Ivanisenko, were analyzed using robust linear regression with Huber’s M-estimates, and a number of metabolites N.V.; Gaisler, E.V.; Oleshko, O.S.; with correlated content in plasma and CSF was identified.
    [Show full text]
  • Metabolic Cooperation Between Di€Erent Oncogenes During
    Oncogene (2001) 20, 6891 ± 6898 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Metabolic cooperation between dierent oncogenes during cell transformation: interaction between activated ras and HPV-16 E7 Sybille Mazurek*,1,4, Werner Zwerschke2,3,4, Pidder Jansen-DuÈ rr2 and Erich Eigenbrodt1 1Institute for Biochemistry and Endocrinology, Veterinary Faculty, University of Giessen, Frankfurter Strasse 100, 35392 Giessen, Germany; 2Institute for Biomedical Ageing Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria; 3Tyrolean Cancer Research Institute, Innrain 66, A-6020 Innsbruck, Austria The metabolism of tumor cells (tumor metabolome) is linked to the disadvantage that those cells undergo characterized by a high concentration of glycolytic apoptosis under glucose limitation (Carmeliet et al., enzymes including pyruvate kinase isoenzyme type M2 1998; Shim et al., 1998). Glucose limitation is also (M2-PK), a high glutaminolytic capacity, high fructose found in solid tumors. To circumvent this disadvan- 1,6-bisphosphate (FBP) levels and a low (ATP+ tage, tumor cells use the amino acids glutamine and GTP):(CTP+UTP) ratio. The sequence of events serine as alternative sources for energy production. In required for the establishment of the tumor metabolome analogy to glycolysis the conversion of glutamine to is presently unknown. In non-transformed rat kidney lactate has been termed glutaminolysis; the ¯ow of (NRK) cells we observed a high glutaminolytic ¯ux rate serine to lactate has been termed serinolysis (Eigen- and a low (ATP+GTP):(CTP+UTP) ratio, whereas brodt et al., 1998a; Mazurek et al., 2001a,b). FBP levels and M2-PK activity are still extremely low.
    [Show full text]
  • Signaling Pathways That Overactivate Metabolism and Drive Neoplasia, in Rhabdomyosarcoma
    Journal of Research and Practice on the Musculoskeletal System JOURNAL OF RESEARCH AND PRACTICE ON THE MUSCULOSKELETAL SYSTEM Review Article Signaling pathways that overactivate metabolism and drive neoplasia, in rhabdomyosarcoma Christos P. Tselios1,2, George I. Lambrou1,2,3 1Laboratory for Research of the Musculoskeletal System “Th. Garofalidis”, Medical School, National and Kapodistrian University of Athens, General Hospital of Athens KAT, Greece; 2Postgraduate Program “Metabolic Bones Diseases”, National and Kapodistrian University of Athens, Medical School, Athens, Greece; 3First Department of Pediatrics, National and Kapodistrian University of Athens, Choremeio Research Laboratory, Goudi, Athens, Greece Abstract The functional status of a cell is expressed in its metabolic activity. Cancer cells differ from normal cells through unlimited cell division, and show a greater need for energy for their rapid growth and duplication. Thus, cancer- associated metabolic alterations, i.e. metabolic over-activation through signaling pathways alterations, have emerged as a cancer hallmark. Rhabdomyosarcoma (RMS) is a myogenic tumor classified as the most frequent soft tissue sarcoma affecting children, adolescents and adults. Signaling pathway alterations present in this cancer can be related to increased metabolic activity and drive neoplasia. In this review first of all, we would like to enlighten cancer and particular RMS metabolism. Further, we aim to summarize several pathways related to oncogenic drivers affecting metabolism of RMS cells in order to simulate them (in other studies) with a system biology approach. The understanding of the common mechanisms that transform physiological cells to malignant may reveal novel therapeutic targets and strategies that may improve the currently poor outcome for patients with RMS.
    [Show full text]