title: The effect of environmental chemicals on the tumor microenvironment.
abstract: Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.
authors.affiliation: Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA 94305, USA, Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy, Department of Pathology, Kuwait University, 13110 Safat, Kuwait, Department of Experimental and Clinical Medicine, University of Firenze, 50134 Florence, Italy, Department of Radiation Oncology, NYU School of Medicine, New York, NY 10016, USA, Department of Environmental and Radiological Health Sciences, Colorado State University/ Colorado School of Public Health, Fort Collins, CO 80523-1680, USA, Centre De Recherche En Cancerologie De Lyon, U1052-UMR5286, Université de Lyon, 69007 Lyon, France, Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way, CB2 0RE Cambridge, UK, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA, Mediterranean Institute of Oncology, 95029 Viagrande, Italy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia, Charles University in Prague, Third Faculty of Medicine, 100 00 Prague 10, Czech Republic, Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia, Department of Science and Biomedical Technology, University of Cagliari, 09124 Cagliari, Italy, Pathology Unit, Mediterranean Institute of Oncology, 95029 Viagrande, Italy, Institute of Molecular Genetics, National Research Council, 27100 Pavia, Italy, Regulatory Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada, Department of Medicine, University of Louisville, Louisville, KY 40202, USA, Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA, University of Pennsylvania School of Medicine
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Casey
authors.affiliation: Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Vaccari
authors.affiliation: Department of Pathology, Kuwait University, 13110 Safat, Kuwait.
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
authors.affiliation: Department of Pathology, Kuwait University, 13110 Safat, Kuwait.
authors.forename: Rabeah
authors.initials: R
authors.lastname: Al-Temaimi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, 50134 Florence, Italy.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Amedei
authors.affiliation: Department of Radiation Oncology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Mary Helen
authors.initials: MH
authors.lastname: Barcellos-Hoff
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University/ Colorado School of Public Health, Fort Collins, CO 80523-1680, USA.
authors.forename: Dustin G
authors.initials: DG
authors.lastname: Brown
authors.affiliation: Centre De Recherche En Cancerologie De Lyon, U1052-UMR5286, Université de Lyon, 69007 Lyon, France.
authors.forename: Marion
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authors.lastname: Chapellier
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way, CB2 0RE Cambridge, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Christopher
authors.affiliation: School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Colleen S
authors.initials: CS
authors.lastname: Curran
authors.affiliation: Mediterranean Institute of Oncology, 95029 Viagrande, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Forte
authors.affiliation: Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia.
authors.forename: Roslida A
authors.initials: RA
authors.lastname: Hamid
authors.affiliation: Charles University in Prague, Third Faculty of Medicine, 100 00 Prague 10, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Heneberg
authors.affiliation: Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA 94305, USA, Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy, Department of Pathology, Kuwait University, 13110 Safat, Kuwait, Department of Experimental and Clinical Medicine, University of Firenze, 50134 Florence, Italy, Department of Radiation Oncology, NYU School of Medicine, New York, NY 10016, USA, Department of Environmental and Radiological Health Sciences, Colorado State University/ Colorado School of Public Health, Fort Collins, CO 80523-1680, USA, Centre De Recherche En Cancerologie De Lyon, U1052-UMR5286, Université de Lyon, 69007 Lyon, France, Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way, CB2 0RE Cambridge, UK, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA, Mediterranean Institute of Oncology, 95029 Viagrande, Italy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia, Charles University in Prague, Third Faculty of Medicine, 100 00 Prague 10, Czech Republic, Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia, Department of Science and Biomedical Technology, University of Cagliari, 09124 Cagliari, Italy, Pathology Unit, Mediterranean Institute of Oncology, 95029 Viagrande, Italy, Institute of Molecular Genetics, National Research Council, 27100 Pavia, Italy, Regulatory Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada, Department of Medicine, University of Louisville, Louisville, KY 40202, USA, Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA, University of Pennsylvania School of Medicine
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koch
authors.affiliation: Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia.
authors.forename: P K
authors.initials: PK
authors.lastname: Krishnakumar
authors.affiliation: Department of Science and Biomedical Technology, University of Cagliari, 09124 Cagliari, Italy.
authors.forename: Ezio
authors.initials: E
authors.lastname: Laconi
authors.affiliation: Centre De Recherche En Cancerologie De Lyon, U1052-UMR5286, Université de Lyon, 69007 Lyon, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Maguer-Satta
authors.affiliation: Department of Science and Biomedical Technology, University of Cagliari, 09124 Cagliari, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Marongiu
authors.affiliation: Pathology Unit, Mediterranean Institute of Oncology, 95029 Viagrande, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Memeo
authors.affiliation: Institute of Molecular Genetics, National Research Council, 27100 Pavia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Mondello
authors.affiliation: Regulatory 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: Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Roman
authors.affiliation: Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA.
authors.forename: Rabindra
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authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University/ Colorado School of Public Health, Fort Collins, CO 80523-1680, USA.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Ryan
authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ryeom
authors.affiliation: Urology Department, Kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 11562, Egypt.
authors.forename: Hosni K
authors.initials: HK
authors.lastname: Salem
authors.affiliation: Institute of Molecular Genetics, National Research Council, 27100 Pavia, Italy.
authors.forename: A Ivana
authors.initials: AI
authors.lastname: Scovassi
authors.affiliation: Centre for Advanced Research, King George's Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India.
authors.forename: Neetu
authors.initials: N
authors.lastname: Singh
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO) and Institució Catalana de Recerca i Estudis Avançats (ICREA), 08035 Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Soucek
authors.affiliation: Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Vermeulen
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO) and Institució Catalana de Recerca i Estudis Avançats (ICREA), 08035 Barcelona, Spain.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Whitfield
authors.affiliation: Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA.
authors.forename: Jordan
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authors.lastname: Woodrick
authors.affiliation: Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colacci
authors.affiliation: Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA, and.
authors.forename: William H
authors.initials: WH
authors.lastname: Bisson
authors.affiliation: Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA 94305, USA dfelsher@stanford.edu.
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced; D004781:Environmental Exposure / Q000009:adverse effects*; D015386:Hazardous Substances / Q000009:adverse effects*; D006801:Humans; D009369:Neoplasms / Q000139:chemically induced; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D015386:Hazardous Substances