title: Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis?
abstract: Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the development and selection of cancer are suggested.
authors.affiliation: Research and Development Service, Veterans Affairs Medical Center, White River Junction, VT 05009, USA, Departments of Medicine and of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH 03756, USA, R.Brooks.Robey@Dartmouth.edu.
authors.forename: R Brooks
authors.initials: RB
authors.lastname: Robey
authors.affiliation: Departments of Gynecology and Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Weisz
authors.affiliation: Research and Development Service, Veterans Affairs Medical Center, White River Junction, VT 05009, USA, Departments of Medicine and of.
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Kuemmerle
authors.affiliation: Departments of Gynecology and Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Salzberg
authors.affiliation: Departments of Gynecology and Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Berg
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523, USA.
authors.forename: Dustin G
authors.initials: DG
authors.lastname: Brown
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, NC 27708, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Kubik
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, 20126, Italy, SYSBIO Center for Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan 20126, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Palorini
authors.affiliation: Department of Pathology, Kuwait University, Safat 13110, Kuwait.
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
authors.affiliation: Department of Pathology, Kuwait University, Safat 13110, Kuwait.
authors.forename: Rabeah
authors.initials: R
authors.lastname: Al-Temaimi
authors.affiliation: Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna, 40126, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colacci
authors.affiliation: Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Mondello
authors.affiliation: Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada.
authors.forename: Jayadev
authors.initials: J
authors.lastname: Raju
authors.affiliation: Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057 USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Woodrick
authors.affiliation: Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy.
authors.forename: A Ivana
authors.initials: AI
authors.lastname: Scovassi
authors.affiliation: Advanced Molecular Science Research Centre, King George's Medical University, Lucknow Uttar Pradesh 226003, India.
authors.forename: Neetu
authors.initials: N
authors.lastname: Singh
authors.affiliation: Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna, 40126, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Vaccari
authors.affiliation: Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057 USA.
authors.forename: Rabindra
authors.initials: R
authors.lastname: Roy
authors.affiliation: Mediterranean Institute of Oncology, Viagrande 95029, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Forte
authors.affiliation: Mediterranean Institute of Oncology, Viagrande 95029, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Memeo
authors.affiliation: Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo, 12515, Egypt.
authors.forename: Hosni K
authors.initials: HK
authors.lastname: Salem
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, Firenze, 50134, Italy.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Amedei
authors.affiliation: Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Roslida A
authors.initials: RA
authors.lastname: Hamid
authors.affiliation: Department of Molecular Medicine, University of Reading, Reading RG6 6UB, UK.
authors.forename: Graeme P
authors.initials: GP
authors.lastname: Williams
authors.affiliation: Centre for Biophotonics, LEC, Lancaster University, Bailrigg, Lancaster LA1 4YQ, UK, Getting to Know Cancer, Truro, Nova Scotia B2N 1X5, Canada, and.
authors.forename: Leroy
authors.initials: L
authors.lastname: Lowe
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, NC 27708, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Meyer
authors.affiliation: Centre for Biophotonics, LEC, Lancaster University, Bailrigg, Lancaster LA1 4YQ, UK.
authors.forename: Francis L
authors.initials: FL
authors.lastname: Martin
authors.affiliation: Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Bisson
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, 20126, Italy, SYSBIO Center for Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan 20126, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Chiaradonna
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523, USA.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Ryan
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced* / Q000378:metabolism*; D002274:Carcinogens, Environmental / Q000009:adverse effects*; D004781:Environmental Exposure / Q000009:adverse effects*; D006801:Humans; D009369:Neoplasms / Q000139:chemically induced* / Q000209:etiology / Q000378:metabolism*
chemical_list: D002274:Carcinogens, Environmental