Modes of Action of Non-Genotoxic Carcinogenesis:
Recent Advances in the Light of Human Relevance
Programme of the Session
A mechanism-based testing strategy to identify non-genotoxic carcinogens
Mirjam Luijten1, Evelyn Olthof1, Betty Hakkert2, Emiel Rorije2, Jan Willem van der Laan3, Ruud Woutersen4, Jan van Benthem1
1Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands; 2Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
Receptor-mediated non-genotoxic carcinogenesis in experimental models: implications for human risk
Colin Henderson1, Aileen McLaren1, Rita Moreno Dorta1, Elke Zabinsky2, Michael Schwarz2, Roland Wolff1, Albert Braeuning3
1Division of Cancer Research, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom; 2Department of Toxicology, University of Tübingen, Institute of Pharmacology and Toxicology, Wilhelmstr. 56, Tübingen, Germany; 3Department of Food Safety, Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany
Late effects of early exposures to endocrine disrupting chemicals in rats
Julie Boberg, Ulla Hass
Division of Diet, Disease Prevention and Toxicology, Technical University of Denmark, Lyngby, Denmark
Integrating genetics, epigenomics and transcriptomics to elucidate mechanisms of xenobiotic-induced non-genotoxic carcinogenesis
Jonathan Moggs, Alberto Del Rio Espinola, Antonio Vitobello, Remi Terranova
Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland
Mesenchyme-derived growth factors/cytokines: Crucial for tumor promotion by non-genotoxic hepatocarcinogens
Bettina Grasl-Kraupp, Marzieh Nejabat, Teresa Riegler, Wolfgang Huber, Rolf Schulte-HermannInstitute of Cancer Research, Medical University Vienna, Vienna, Austria
Environmental immune disruptors, inflammation and carcinogenesis: a state of the science and new horizons
William H. Bisson
Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States
In the safety evaluation of substances, carcinogenesis is a major toxicity endpoint. Most of the current test strategies focus on proving the absence of genotoxicity. Therefore, non-genotoxic carcinogens (NGC) may remain unidentified, which may pose a substantial risk to society and environment. To fill this gap, M. Luijten will provide information on the mode of action of NGC and adequate testing strategies.
NGC often act as ligands of nuclear receptors, which may be causally involved in carcinogenesis. C. Henderson has developed transgenic mouse models, reporter lines, and mice humanized for nuclear receptors to enable the identification of critical, cancer-related effects of NGC being of significance for human carcinogenesis.
Endocrine disrupting compounds may interfere with tissues at critical developmental stages. Cell populations may be generated giving rise to cancer later in life. J. Boberg will focus on early-life exposure to endocrine disrupting compounds which is associated with increased risk for carcinogenesis in mammary and prostate glands in experimental models. The human relevance of these findings will be discussed.
J. Moggs will present opportunities to leverage recent advances in the molecular understanding of non-genotoxic carcinogenesis. This will enhance preclinical mechanistic interpretation of drug-induced carcinogenicity and the identification of early molecular indicators of neoplasia, with a particular focus on tissue-specific epigenetic modifications and biomarkers of de-differentiation/reprogramming within adult tissues.
B. Grasl-Kraupp will focus on experimental evidence for NGC-induced alterations in the functional state of the liver mesenchyme. As a result, pro-inflammatory cytokines and growth factors are released from mesenchymal cells which may act on early tumor stages and trigger the development of liver tumors. The significance of these experimental findings for human hepatocarcinogenesis will be discussed.
W. Bisson will report on environmental ubiquitous chemicals such as bisphenol A or phthalates. These compounds are non-genotoxic and act on immune cells and molecular targets mechanistically linked to cancer associated inflammation. Experimental models and epidemiological studies will be used to investigate if these chemicals influence cancer risk in humans.