The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling

Carcinogenesis, 2015, Vol. 36, Supplement 1, S38–S60 doi:10.1093/carcin/bgv030 Review review The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden, 2School of Biological Sciences, University of Reading, Whiteknights, Reading RG6 6UB, UK, 3Department of Biochemistry, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Box 575, 75123 Uppsala, Sweden, 4Faculty of Medicine, University of Otago, PO Box 913, Dunedin 9050, New Zealand, 5Department of Biological Chemistry Medical School, Institute of Molecular Medicine and Biomedical Research, University of Athens, Marasli 3, Kolonaki, Athens 10676, Greece, 6Department of Environmental Health, School of Public Health, Indiana University Bloomington, 1025 E. 7th Street, Suite 111, Bloomington, IN 47405, USA, 7Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, HPFB, Health Canada, 251 Sir F.G. Banting Driveway, AL # 2202C, Tunney’s Pasture, Ottawa, Ontario K1A 0K9, Canada, 8Department of Biochemistry and Biology, University of Bath, Claverton Down, Bath BA2 7AY, UK, 9INRS-Institut Armand-Frappier, 531 boulevard des Prairies, Laval, Quebec H7V 1B7, Canada, 10Environmental Exposure Research Section, Center for Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibraki 3058506, Japan, 11IRC in Biomedical Materials, School of Engineering & Materials Science, Queen Mary University of London, Mile End Road, London E1 4NS, UK, 12Center for Stem Cell Research and Development, Hacettepe University, Ankara 06100, Turkey, 13Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India, 14Department of Pathology, Kuwait University, Safat 13110, Kuwait, 15Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy, 16Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy, 17Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy, 18Regulatoty Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, HPFB, Health Canada, Ottawa, Ontario K1A0K9, Canada, 19Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia, 20Mediterranean Institute of Oncology, Viagrande 95029, Italy, 21Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA, 22Urology Dept. kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt, 23Department of Environmental and Radiological Sciences, Colorado State University//Colorado School of Public Health, Fort Collins CO 80523-1680, USA and 24Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA 1 Received: February 22, 2014; Revised: December 9, 2014; Accepted: December 15, 2014 © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: . S38 Wilhelm Engström1,*, Philippa Darbre2, Staffan Eriksson3, Linda Gulliver4,†, Tove Hultman1,2, Michalis V.Karamouzis5, James E.Klaunig6, Rekha Mehta7, Kim Moorwood8, Thomas Sanderson9, Hideko Sone10, Pankaj Vadgama11, Gerard Wagemaker12, Andrew Ward8, Neetu Singh13,‡, Fahd Al-Mulla14,‡, Rabeah Al-Temaimi14,‡, Amedeo Amedei15,‡, Anna Maria Colacci16,‡, Monica Vaccari16,‡, Chiara Mondello17,‡, A.Ivana Scovassi17,‡, Jayadev Raju18,‡, Roslida A.Hamid19,‡, Lorenzo Memeo20,‡, Stefano Forte20,‡, Rabindra Roy21,‡, Jordan Woodrick21,‡, Hosni K.Salem22,‡, Elizabeth P.Ryan23,‡, Dustin G.Brown23,‡ and William H.Bisson24,‡ W.Engström et al. | ‡ † S39 Members of the cross-validation team responsible for the compilation of Tables 2 and 3. Responsible for the main validation as presented in Supplementary Table 1. *To whom correspondence should be addressed. Tel: +4618671000; Fax: +4618673532; Email: Abstract The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span. AhR AP-1 AR CDK DHT EGF ER IL MAPK mTOR mTORC NP PAH PI PI3K PKC PP2A PPAR PTEN Rb siRNA SRD5A TGF-β aryl hydrocarbon receptor activator protein 1 androgen receptor cyclin-dependent kinase dihydrotestosterone epidermal growth factor oestrogen receptor interleukin mitogen-activated protein kinase mammalian target of rapamycin mTOR complex nanoparticle polycyclic aromatic hydrocarbon phosphatidylinositol PI-3-kinase protein kinase C protein phosphatase 2A peroxisome proliferator-activated receptor phosphatase and tensin homolog retinoblastoma small interfering RNA steroid 5-alpha reductase transforming growth factor-β Introduction In two classical articles, Hanahan et al. (1,2) introduced the term ‘Hallmarks of Cancer’ to constitute an organizing principle that provides a logical framework for understanding ‘the remarkable diversity of neoplastic diseases’. The basis for this new concept was the idea that as normal cells undergo step-by-step transformation towards neoplasia, they acquire a succession of hallmark capabilities. Hanahan et al. argued that tumours are more than insular masses of proliferating malignant cells. Instead, they are complex tissues composed of multiple distinct cell types that participate in heterotypic interactions with one another. Recruited normal cells, which build up the surrounding stroma, play an active role in tumourigenesis rather than act as passive bystanders. Thus, stromal cells contribute to the action of certain hallmark capabilities. The hallmarks of cancer include six core attributes, namely sustained proliferative signalling, evading growth suppression, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis and resisting cel (...truncated)