Carcinogenesis, Vol. 20, No. 4, 519-527,
April 1999
© 1999 Oxford University Press
Review |
Environmental factors as regulators and effectors of multistep carcinogenesis
Ruttenberg Cancer Center, Mount Sinai School of Medicine, One Gustave L.Levy Place, Box 1130, New York, NY 10029, USA and
1 Cancer Research Institute Kanazawa University, Kanazawa, Japan
This review highlights current knowledge of environmental factors in carcinogenesis and their cellular targets. The hypothesis that environmental factors influence carcinogenesis is widely supported by both epidemiological and experimental studies. The fact that only a small fraction of cancers can be attributed to germline mutations in cancer-related genes further buttresses the importance of environmental factors in carcinogenesis. Furthermore, penetrance of germline mutations may be modified by either environmental or other genetic factors. Examples of environmental factors that have been associated with increased cancer risk in the human population include chemical and physical mutagens (e.g. cigarette smoke, heterocyclic amines, asbestos and UV irradiation), infection by certain viral or bacterial pathogens, and dietary non-genotoxic constituents (e.g. macro- and micronutrients). Among molecular targets of environmental influences on carcinogenesis are somatic mutation (genetic change) and aberrant DNA methylation (epigenetic change) at the genomic level and post-translational modifications at the protein level. At both levels, changes elicited affect either the stability or the activity of key regulatory proteins, including oncoproteins and tumor suppressor proteins. Together, via multiple genetic and epigenetic lesions, environmental factors modulate important changes in the pathway of cellular carcinogenesis.
Abbreviations: CREB, cyclic AMP response element binding protein; EGFR, epidermal growth factor receptor; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HPV, human papilloma virus; IGFR, insulin-like growth factor receptor; MAPK, mitogen activated protein kinase; NO, nitric oxide; PKA, protein kinase A; PKC, protein kinase C; ROS, reactive oxygen species; TFIIH, transcription factor IIH; TPA, 12-O-tetradecanoylphorbol-13-acetate.
2 To whom correspondence should be addressed
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