• 1 Spanish National Cancer Research Center, Experimental Therapuetics Department, Melchor Fernandez Almagro, 3, 28029 Madrid, Spain
  • 2 Department of Geriatric Medicine, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku Kyoto 606-8507, Japan
  • 3 Institut De Recerca Hospital Vall D'Hebron, Passeig Vall d'Hebron, 119-129, 08035 Barcelona, Spain
  • 4 Cell Biology Department, Pharmamar-SAU, Avda. De los Reyes, 1, 28770-Colmenar Viejo, Madrid, Spain
  • 5 Istituto di Genetica Molecolare, CNR, Via Abbiategrasso 207, 27100 Pavia, Italy
  • 6 Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA
  • 7 Department of Experimental and Clinical Medicine, University of Firenze, Italy, Florence 50134, Italy
  • 8 Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
  • 9 Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
  • 10 Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
  • 11 Department of Pathology, Kuwait University, Safat 13110, Kuwait
  • 12 Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
  • 13 Mediterranean Institute of Oncology, Viagrande 95029, Italy
  • 14 Centre for Advanced Research, King George's Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
  • 15 Department of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor 43400, Malaysia
  • 16 Department of Environmental and Radiological Health Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
  • 17 The Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth Street, Portland, ME 04104, USA and
  • 18 Brunel Institute of Cancer Genetics and Pharmacogenomics, Health and Environment Theme, Institute of Environment, Health and Societies, Brunel University London, Kingston Lane, Uxbridge, UB8 3PH, UK
Carcinogenesis, 2015 Jun;36 Suppl 1:S19-37.
PMID: 26106138 DOI: 10.1093/carcin/bgv029


Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated 'selection and succession' of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of 'driver mutations' enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? What are the underlying mechanisms responsible for chemical carcinogen-induced cellular immortality? Here, we explore the possible mechanisms of cellular immortalization, the contribution of immortalization to tumorigenesis and the mechanisms by which chemical carcinogens may contribute to these processes.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.