DOCSLIB.ORG

Correlation of Metabolic Profiles of Plasma and Cerebrospinal Fluid Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read 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. The statistical analysis shows a significant Cheresiz, S.V.; Mishinov, S.V.; Stupak, V.V.; Pokrovsky, A.G. Correlation of correlation of metabolite content in plasma and CSF samples for the majority of metabolites. Several Metabolic Profiles of Plasma and metabolites were shown to have high correlation in the control samples, but not in the glioma patients. Cerebrospinal Fluid of High-Grade This can be due to the specific metabolic processes in the glioma patients or to the damaged integrity Glioma Patients. Metabolites 2021, 11, of blood-brain barrier. The results of our study may be useful for the understanding of molecular 133. https://doi.org/10.3390/ mechanisms underlying the development of gliomas, as well as for the search of potential biomarkers metabo11030133 for the minimally invasive diagnostic procedures of gliomas. Academic Editors: Peter Meikle and Keywords: glioma; metabolomics; liquid chromatography; tandem mass spectrometry; plasma; Thusitha W. Rupasinghe cerebrospinal fluid Received: 21 December 2020 Accepted: 22 February 2021 Published: 25 February 2021 1. Introduction Publisher’s Note: MDPI stays neutral Gliomas, which represent the majority (81%) of malignant brain tumors, are classified with regard to jurisdictional claims in using WHO grade criteria into 4 grades based on increasing degree of anaplasia and aggres- published maps and institutional affil- siveness, with malignant gliomas comprising grades III and IV tumors. The most prevalent iations. glioma types include astrocytoma (WHO grade I–IV), oligodendroglioma (WHO grade II– III), and oligoastrocytomas (WHO grade II–III). High-grade gliomas include glioblastoma (WHO Grade IV astrocytoma), anaplastic (WHO Grade III) astrocytoma, anaplastic (WHO Grade III) oligodendroglioma and mixed (WHO Grade III) oligoastrocytomas [1,2]. The most common type of glioma is glioblastoma, which accounts for 82% of malignant Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. gliomas and has the worst survival prognosis, with only 5% of patients surviving 5 years This article is an open access article after diagnosis [1,2]. The 5-year survival rates for Grade III malignant gliomas are signif- distributed under the terms and icantly higher (~25% for anaplastic astrocytoma, 45% for anaplastic oligodendroglioma conditions of the Creative Commons and ~50% for mixed oligoastrocytic tumors [1]. A multimodal treatment including surgical Attribution (CC BY) license (https:// removal of tumor with a concomitant/adjuvant radio- and chemotherapy (temozolomide) creativecommons.org/licenses/by/ is the first-line standard-of-care for glioblastoma, the use of which increased the median 4.0/). survival to 15 months vs 12 months with radiotherapy alone [2]. Metabolites 2021, 11, 133. https://doi.org/10.3390/metabo11030133 https://www.mdpi.com/journal/metabolites Metabolites 2021, 11, 133 2 of 13 Although the clinical point of view exists that early diagnosis (and treatment) do not improve the outcomes in glioblastoma, an alternative opinion suggests that an early diagnosis and accurate tumor classification must become a cornerstone of an efficient personalized therapy [3]. In fact, the current diagnostic procedure for glioblastoma always results in a late diagnosis, since it relies on neurological tests and neuroimaging. Meanwhile, numerous studies underscore the importance of a maximum surgical removal of tumor mass up to the borders of the healthy surrounding tissue for a better survival and life expectancy of glioblastoma patients [3], which, in case of a brain tumor, is, apparently, less feasible with larger and more advanced late-diagnosed neoplasms. An early diagnosis of a brain tumor is, thus, an important task for the improvement of treatment efficiency and survival of the patients. The development of minimally invasive approaches for the early detection and classification of tumors is indispensable for choosing a more efficient therapeutic strategy. The malignant cells including those of brain tumors have been long known to pos- sess metabolic alterations [4–6]. These features are due to their enhanced survival and reproduction under the conditions when nutrients and oxygen are scarce, which may be caused by the gene mutations resulting in an altered functioning of different enzymatic pathways [7–9]. An apparent difference in the metabolic profiles of normal and malignant cells laid the groundwork for the development of diagnostic methods relying upon the identification of specific disease biomarkers. The study of brain tumor metabolome and the search for biomarkers indicative of brain tumor development and helpful in tumor grading or making the diagnosis of tumor recurrence pose an ongoing challenge, different instrumental approaches to which are being developed. The cerebrospinal fluid (CSF), which is secreted by the choroids plexus and the meninges, and circulates between brain ventricles and spinal subarachnoid space, is in- volved in a number of protection, metabolic and drainage functions. Consisting of ~80% of blood-derived and 20% of brain-derived components and being permanently renewed, it maintains the electrolytic and acid-base balance of the brain and supplies the nutrients and signal molecules to the neuronal and glial cells. Meanwhile, it serves as a lymphatic system for the CNS by draining off the wastes and neurotoxic products of brain metabolism. It also provides mechanical support and protection against brain traumas and is involved in intracranial pressure maintenance. Filtration of blood-derived immune molecules, such as the immunoglobulins and cytokines through the blood-brain barrier (BBB) into the CSF ensures the immunological function of the CSF. Finally, the CSF is directly involved in the circadian cycle control via its prostaglandin D2 (PGD2) and prostaglandin-D-synthase (PGDS) system [10]. The CSF is an important diagnostic tool for the search of biomarkers of brain diseases and dysfunctions. A number of published studies is dedicated to the identification of biomarkers of Parkinson’s and Alzheimer’s diseases, multiple sclerosis, etc. [11–14]. An apparent disadvantage of metabolomic approaches to the CSF analysis is the relative invasiveness of the CSF withdrawal procedure, which requires a lumbar puncture. A number of published studies presents the metabolomic screening for glioma biomark- ers in individual CSF [15,16] or plasma [17,18] samples. Meanwhile, a limited number of studies analyses the relative metabolite content in matched CSF and plasma samples in different pathologies, e.g., Alzheimer disease [19], and neither publication compares the matched CSF and plasma metabolite profiles in the patients with gliomas. Here, we present a wide-range metabolomic analysis of the CSF and blood plasma samples in the groups of glioma patients and conditionally healthy controls, as well as a correlation study of the metabolomic profiles of matched CSF/plasma samples in the individual study subjects. 2. Results and Discussion The plasma and CSF samples were obtained from each participant and analyzed in three replicates. As much as 289 metabolites (Table S1) were screened by HPLC-MS/MS using the approach described by Yuan et al. [20]. This approach consists of a targeted Metabolites 2021, 11, 133 3 of 14 Metabolites 2021, 11, 133 3 of 13 approach described by Yuan et al. [20]. This approach consists of a targeted analysis of metabolitesanalysis of metabolites in MRM mode in MRM using mode positive/negative using positive/negative polarity switching polarity switchingfollowed by followed a rela- tivebya quantitation relative quantitation of the compounds. of the compounds. After analysis After of analysis samples, of the samples, resulting the chromato- resulting gramschromatograms were integrated
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]
  • 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.
    [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]
  • 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]