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Carcinogenesis. 2015 Jun;36 Suppl 1:S203-31. doi: 10.1093/carcin/bgv037.

Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis?

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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,
Departments of Gynecology and Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Research and Development Service, Veterans Affairs Medical Center, White River Junction, VT 05009, USA, Departments of Medicine and of.
Department of Environmental and Radiological Health Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523, USA.
Nicholas School of the Environment, Duke University, Durham, NC 27708, USA.
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.
Department of Pathology, Kuwait University, Safat 13110, Kuwait.
Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna, 40126, Italy.
Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy.
Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada.
Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057 USA.
Advanced Molecular Science Research Centre, King George's Medical University, Lucknow Uttar Pradesh 226003, India.
Mediterranean Institute of Oncology, Viagrande 95029, Italy.
Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo, 12515, Egypt.
Department of Experimental and Clinical Medicine, University of Firenze, Firenze, 50134, Italy.
Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
Department of Molecular Medicine, University of Reading, Reading RG6 6UB, UK.
Centre for Biophotonics, LEC, Lancaster University, Bailrigg, Lancaster LA1 4YQ, UK, Getting to Know Cancer, Truro, Nova Scotia B2N 1X5, Canada, and.
Centre for Biophotonics, LEC, Lancaster University, Bailrigg, Lancaster LA1 4YQ, UK.
Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA.


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.

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