title: Dysregulated metabolism contributes to oncogenesis.
abstract: Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review "Hallmarks of Cancer", where dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results demonstrate that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA; Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: matthew.hirschey@duke.edu.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hirschey
authors.affiliation: Children's Medical Center Research Institute, University of Texas - Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Anna Mae E
authors.initials: AME
authors.lastname: Diehl
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors.forename: Janice E
authors.initials: JE
authors.lastname: Drew
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom.
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Michelle F
authors.initials: MF
authors.lastname: Green
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Lee W
authors.initials: LW
authors.lastname: Jones
authors.affiliation: University of Maryland BioPark, KoDiscovery, Baltimore, MD 20201, USA.
authors.forename: Young H
authors.initials: YH
authors.lastname: Ko
authors.affiliation: The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Le
authors.affiliation: New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lea
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA; Division of Nutritional Sciences, Cornell University, Ithaca, NY 14850, USA; Field of Genetics, Genomics, and Development, Cornell University, Ithaca, NY 14850, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: Andrus Gerontology Center, Division of Biogerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Valter D
authors.initials: VD
authors.lastname: Longo
authors.affiliation: Department of Molecular and Integrative Physiology and Department of Internal Medicine, University of Michigan, Ann Arbor 48109, USA.
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Eoin
authors.initials: E
authors.lastname: McDonnell
authors.affiliation: Field of Genetics, Genomics, and Development, Cornell University, Ithaca, NY 14850, USA.
authors.forename: Mahya
authors.initials: M
authors.lastname: Mehrmohamadi
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Michelotti
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vinayak
authors.initials: V
authors.lastname: Muralidhar
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust-MRC Building, Cambridge, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Department of Biological Chemistry and Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Pedersen
authors.affiliation: The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Poore
authors.affiliation: Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Lizzia
authors.initials: L
authors.lastname: Raffaghello
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA; Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Rathmell
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sharanya
authors.initials: S
authors.lastname: Sivanand
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Wellen
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D044127:Epigenesis, Genetic; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
keywords: Cancer metabolism; Cancer therapy; Host metabolism; Mitochondria; Warburg