title: Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis.
abstract: One of the important 'hallmarks' of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential.
authors.affiliation: Department of Surgery and The James Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, INSERM U1113, team 3 "Cell Signalling and Communication in Kidney and Prostate Cancer", University of Strasbourg, Facultée de Médecine, 67085 Strasbourg, France, Department of Cell and Developmental Biology, University of California, Irvine, CA 92697, USA, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892-3375, USA, Department of Life Sciences, Tzu-Chi University, Taiwan, Republic of China, Department of Microbiology and Immunology, Taipei Medical University, Taiwan, Republic of China, Department of Pathology, Kuwait University, Safat 13110, Kuwait, Department of Experimental and Clinical Medicine, University of Firenze, Florence 50134, Italy, Department of Environmental and Radiological Health Sciences , Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523, USA, Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA, Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna, Italy, Faculty of Medicine and Health Sciences, University Putra, Serdang, Selangor, Malaysia, Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy, Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate , Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA, Advanced Molecular Science Research Centre (Centre for Advance Research), King George's Medical University, Lucknow, Uttar Pradesh 226003, India, Mediterranean Institute of Oncology, Viagrande 95029,
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Samira A
authors.initials: SA
authors.lastname: Brooks
authors.affiliation: INSERM U1113, team 3 "Cell Signalling and Communication in Kidney and Prostate Cancer", University of Strasbourg, Facultée de Médecine, 67085 Strasbourg, France, Department of Cell and Developmental Biology, University of California, Irvine, CA 92697, USA.
authors.forename: Valérian
authors.initials: V
authors.lastname: Dormoy
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892-3375, USA.
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Hsu
authors.affiliation: Department of Life Sciences, Tzu-Chi University, Taiwan, Republic of China.
authors.forename: Hsue-Yin
authors.initials: HY
authors.lastname: Hsu
authors.affiliation: Department of Microbiology and Immunology, Taipei Medical University, Taiwan, Republic of China.
authors.forename: Liang-Tzung
authors.initials: LT
authors.lastname: Lin
authors.affiliation: INSERM U1113, team 3 "Cell Signalling and Communication in Kidney and Prostate Cancer", University of Strasbourg, Facultée de Médecine, 67085 Strasbourg, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Massfelder
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892-3375, USA.
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
authors.affiliation: Department of Life Sciences, Tzu-Chi University, Taiwan, Republic of China.
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: Department of Experimental and Clinical Medicine, University of Firenze, Florence 50134, Italy.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Amedei
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: Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Kalan R
authors.initials: KR
authors.lastname: Prudhomme
authors.affiliation: Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colacci
authors.affiliation: Faculty of Medicine and Health Sciences, University Putra, Serdang, Selangor, Malaysia.
authors.forename: Roslida A
authors.initials: RA
authors.lastname: Hamid
authors.affiliation: Institute of Molecular Genetics, National Research Council, Pavia 27100, 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 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
authors.affiliation: 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 (Centre for Advance Research), 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, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Vaccari
authors.affiliation: 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: Getting to Know Cancer, Truro, Nova Scotia B2N 1X5, Canada.
authors.forename: Leroy
authors.initials: L
authors.lastname: Lowe
authors.affiliation: Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden and.
authors.forename: Lasse
authors.initials: L
authors.lastname: Jensen
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: Integrated Laboratory Systems, Inc., in support of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, NIEHS, MD K2-16, RTP, NC 27709, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kleinstreuer
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced*; D002274:Carcinogens, Environmental / Q000009:adverse effects*; D004781:Environmental Exposure / Q000009:adverse effects*; D015386:Hazardous Substances / Q000009:adverse effects*; D006801:Humans; D009369:Neoplasms / Q000139:chemically induced* / Q000209:etiology*; D009389:Neovascularization, Pathologic / Q000139:chemically induced*
chemical_list: D002274:Carcinogens, Environmental; D015386:Hazardous Substances