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.

Cancer Research UK Cambridge Institute University of Cambridge Robinson Way CB2 0RE Cambridge UK

Center for Environment and Water Research Institute King Fahd University of Petroleum and Minerals Dhahran 31261 Saudi Arabia

Center for Environmental Carcinogenesis and Risk Assessment Environmental Protection and Health Prevention Agency 40126 Bologna Italy

Center for Experimental Molecular Medicine Meibergdreef 9 1105 AZ Amsterdam The Netherlands

Centre De Recherche En Cancerologie De Lyon U1052 UMR5286 Université de Lyon 69007 Lyon France

Centre for Advanced Research King George's Medical University Chowk Lucknow Uttar Pradesh 226003 India

Charles University Prague 3rd Faculty of Medicine 100 00 Prague 10 Czech Republic

Department of Environmental and Molecular Toxicology Environmental Health Sciences Center Oregon State University Corvallis OR 97331 USA and

Department of Environmental and Radiological Health Sciences Colorado State University Colorado School of Public Health Fort Collins CO 80523 1680 USA

Department of Experimental and Clinical Medicine University of Firenze 50134 Florence Italy

Department of Medicine University of Louisville Louisville KY 40202 USA

Department of Pathology Kuwait University 13110 Safat Kuwait

Department of Radiation Oncology NYU School of Medicine New York NY 10016 USA

Department of Science and Biomedical Technology University of Cagliari 09124 Cagliari Italy

Division of Oncology Departments of Medicine and Pathology Stanford University Stanford CA 94305 USA

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 Prague 3rd 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

Faculty of Medicine and Health Sciences Universiti Putra Malaysia Serdang 43400 Selangor Malaysia

Institute of Molecular Genetics National Research Council 27100 Pavia Italy

Mediterranean Institute of Oncology 95029 Viagrande Italy

Molecular Oncology Program Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington DC 20057 USA

Pathology Unit Mediterranean Institute of Oncology 95029 Viagrande Italy

Regulatory Toxicology Research Division Bureau of Chemical Safety Food Directorate Health Products and Food Branch Health Canada Ottawa Ontario K1A0K9 Canada

School of Medicine and Public Health University of Wisconsin Madison Madison WI 53705 USA

University of Pennsylvania School of Medicine Philadelphia PA 19104 USA

Urology Department Kasr Al Ainy School of Medicine Cairo University El Manial Cairo 11562 Egypt

Vall d'Hebron Institute of Oncology 08035 Barcelona Spain

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