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Assessing the Carcinogenic Potential of Low Dose Exposures to Chemical Mixtures in the Environment

This Halifax Project task force focused on "Assessing the Carcinogenic Potential of Low Dose Exposures to Chemical Mixtures in the Environment". 174 scientists from prominent institutions in 28 countries were formed into 12 teams (see below) and they focused on the possibility that complex mixtures of commonly encountered chemicals in the environment may be capable of carcinogenic effects that have yet to be fully appreciated. This project was initiated because we believe that the historical scientific and regulatory emphasis on “mutagens as carcinogens” and the ongoing search for individual chemicals and precisely defined mixtures that are “complete” carcinogens (i.e., can cause cancer on their own) is an incomplete approach that has serious limitations. The last few decades have shown us that cancer can be enabled by a series of key events, while chemical exposure research has shown us that many of these key events can be independently instigated. At the same time, we have discovered that many chemicals have low dose effects that have not been fully appreciated. So this task force looked at the possibility that exposures to mixtures of disruptive chemicals at low doses (in our day-to-day lives) might be contributing to the high rates of cancer incidence that society is currently facing.

From the thousands of chemicals to which the population is now routinely exposed, the scientists selected 85 prototypic chemicals that were not considered to be carcinogenic to humans and they reviewed their effects against a long list of mechanisms that are important for cancer development.  Working in teams that focused on various hallmarks of cancer, the group found that 50 of those chemicals support key cancer-related mechanisms at environmentally-relevant levels of exposure.  This supports the idea that chemicals may be capable of acting in concert with one another to cause cancer, even though low level exposures to these chemicals individually might not be carcinogenic.  This is a paradigm shift in the field of toxicology and the research has now been published in Oxford's Carcinogenesis (click here to see the special issue). 

The teams that worked on this effort are shown below.

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Zhiwei Hu MD, PhD, Ohio State University (United States) - Associate professor in the Department of Surgery of The Ohio State University College of Medicine. Dr. Hu is one of first few scientists who proposed to target both the tumor cells and tumor neovasculature for development of novel dual neovascular- and cancer cell-targeted therapy for cancer. Currently his laboratory is focusing on further elucidating the mechanisms of action and improving the efficacy of factor VII-targeted immunotherapy and photodynamic therapy for human cancers. His laboratory is also studying tumor angiogenesis, natural killer cells and cancer stem cells and their interaction in tumor microenvironment.
Click here to view entire team
Deregulated metabolism
R. Brooks Robey, MD FASN FAHA, Dartmouth College & White River Junction VA Medical Center (United States) - Dr. Robey is both Associate Chief of Staff for Research and Founding Chief of the Section of Nephrology at the White River Junction VA Medical Center. He also holds dual academic appointments at The Geisel School of Medicine at Dartmouth, where he is an Associate Professor of Medicine and of Physiology and Neurobiology, as well as a faculty member of Dartmouth's Program in Experimental and Molecular Medicine. His scientific interests include the regulation of cellular metabolism and metabolic determinants of cell survival and apoptogenic susceptibility. His laboratory specifically focuses on the regulation and functional contributions of hexokinases.
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Evasion of Anti-growth Signalling
Rita Nahta, PhD, Emory University (United States) - Assistant Professor at the Emory University School of Medicine, Department of Pharmacology, and the Winship Cancer Institute, Emory University in Atlanta, Georgia. Dr Nahta focuses on the biological and therapeutic implications of growth factor signaling crosstalk in breast cancer. Significant advances in the treatment of metastatic breast cancer include the development of therapies targeted against specific cancer-causing molecules. However, the success of these mono-targeted therapies is often limited by cross-talk between multiple signaling pathways. Dr Nahta is specifically interested in understanding how cross-talk between HER2 and other growth factor signaling pathways affects the biology of HER2-overexpressing breast cancers, including how signaling cross-talk promotes resistance to targeted therapies.
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Genetic Instability
Andrew Collins, PhD, ScD, University Of Oslo (Norway) - Professor, Nutritional Biology. Dr Collin's early research was focused on molecular mechanisms of DNA repair in mammalian cells, and in particular the manipulation of repair with the use of DNA synthesis inhibitors, which allowed identification of mutant phenotypes and analysis of the kinetics of repair. He then developed an interest in oxidative damage to DNA, and the ability of phytochemicals to protect against this damage, pioneering a molecular epidemiological approach using the comet assay to measure DNA damage in lymphocytes from human subjects. Dr Collins also co-ordinated an international effort (ESCODD) to deal with serious methodological problems in the measurement of DNA oxidation. His lab has also developed high throughput biomarker assays for DNA damage and repair for use in large-scale human trials, in combination with genotyping. Future efforts will emphasize interactions of environment (including nutrition) with DNA repair phenotype and genotype.
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Immune System Evasion
H. Kim Lyerly MD, FACS, Duke University (United States) - Professor of Cancer Research at Duke University and a senior member of the Duke global health team. He was, until recently, the director of the Duke Comprehensive Cancer Center. In 2008, Dr. Lyerly was appointed to the National Cancer Advisory Board by President George Bush. He was also named by his peers as one of North Carolina's most outstanding clinical physicians. Dr. Lyerly has been a faculty member of the AACR/ASCO Methods in Clinical Cancer Research, and has served as a faculty member of ACORD Workshops. He is currently a member of the Scientific Advisory Board of Susan G. Komen for the Cure and the Burroughs Wellcome Foundation.
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Replicative Immortality
Amancio Carnero Moya, PhD, Institute Of Biomedicine Of Sevilla (Spain) - Dr Carnero leads the Molecular Biology of Cancer Lab at the Biomedical Institute of Seville (IBIS/CSIC). In the past, his research interests have focused on the ras signal transduction pathway, the cell cycle, senescence and cellular immortalization. His lab is currently focused on the identification and characterization of genes with therapeutic relevance in cancer; establishing causality in the initiation and progression of the tumoral process; and the validation of new therapeutic targets that could form the basis for the identification of new anti-tumor compounds
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Resistance to Apoptosis
Hyun Ho Park, PhD, Yeungnam University (Korea South) - Assistant professor at the Yeungnam University. Dr. Park's group studies protein-protein interactions involved in the intracellular signaling that are closely linked to human health and disease, with an emphasis on cancer. Their main targets are cell death signaling pathways (apoptosis, necrosis, and autophagy), using X-ray crystallography in conjunction with other biochemical and biophysical methods to elucidate the interaction mechanism and protein-protein interface (PPI) at the atomic level. The ultimate goal of Dr Park's research team is to develop chemical or peptide drugs that can regulate targeted signaling pathways.
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Sustained Proliferative Signalling
Wilhelm Engstrom, MD, Swedish University Of Agricultural Sciences (Sweden) - Professor of Pathology in the Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine. Dr. Engstrom's research has primarily been focused on cell cycle regulation and growth factor gene transcription control. His most recent research has focused on fibrous proteins and the relationship between protein structure and biomechanics, as well as epigenetic regulation of growth factor gene expression. He is Chairman of The European Cell Proliferation Society, and a Fellow of both the Royal Society of Sciences in Uppsala and the Royal College of Pathologists (UK).
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Tissue Invasion and Metastasis
Josiah Ochieng, PhD, Meharry Medical College (United States) - Professor in the Department of Cancer Biology and Director of the Cancer Biology Program at Meharry Medical College in Nashville, Tennessee. Dr. Ochieng has investigated the role of fetuin-A (a liver derived glycoprotein) in the progression of solid tumors. The working hypothesis for this project is that fetuin-A, promotes tumor cell growth via exosomes that mediate adhesive and motility signaling mechanisms. Dr. Ochieng believes fetuin-A is not only relevant in the in vitro cell growth (it is the major serum protein in fetal bovine serum) but more importantly, in the in vivo growth of tumor cells in rodents and humans. Cell and molecular biology techniques are used to uncover the mechanisms involved. He believes the exosomes released by fetuin-A in tumor cells are major growth, motility and invasion drivers during cancer metastasis. The long term goal is to define the growth mechanisms involved in this novel pathway.
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Tumor Microenvironment
Dean Felsher, MD, PhD, Stanford University (United States) - Professor of Medicine and of Pathology at Stanford School of Medicine, Stanford University, California, USA. Dr Felsher's research interests include both basic science and translational research studies that investigate how oncogenes initiate and sustain tumorigenesis. He is a 1996 Lymphatic Research Foundation Fellow and 2001 Junior Faculty Award Recipient. His laboratory has developed model systems that can conditionally activate oncogenes in normal human and mouse cells in tissue culture or in specific tissues of transgenic mice.
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Tumor Promoting Inflammation
Patricia Thompson, PhD, The University Of Arizona Cancer Center (United States) - Associate Professor and Director of the Cancer Prevention and Control Program at the University of Arizona. Dr. Thompson is a molecular epidemiologist whose research in breast cancer includes development of molecular marker based risk prediction models of early stage breast cancer to guide patient decision making about treatment. She also has an active research interest in chemoprevention of breast cancer targeting high risk patient populations using non-hormone based therapies like non-steroidal anti-inflammatory agents. She focuses on research related to primary and secondary prevention of colon and breast cancer, and has a specific interest in the role of inflammation in carcinogenesis and the factors that contribute to inflammation.
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Validation Team
William Bisson, PhD, Oregon State University (United States) - Assistant Professor, Department of Environmental and Molecular Toxicology at Oregon State University. Dr Bisson's current research involves computational chemical genomics techniques (molecular modeling, docking, simulations) combined with molecular biology and medicinal chemistry as an inter-disciplinary approach in cancer research for drug design and discovery, to study protein functionality and to understand drug resistance.
In addition, research efforts concentrate on the characterization of dietary compounds for cancer prevention and on understanding of carcinogenesis through the combination of computational approaches and biological studies.
Click here to view entire team

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