Etiology of cancer in humans and animals

Cancer is a multistep disease with a multifactorial aetiology. Among the avoidable causes of human cancer are exposure to environmental carcinogens, ionizing and non-ionizing radiation, chronic inflammatory states (viruses and parasites) and life style factors, in particular diet. There is increasing evidence that these aetiologic factors may interact with each other resulting in a more than additive cancer risk. This has been demonstrated for example with hepatitis B virus and aflatoxins in hepatocellular carcinoma and alcohol and tobacco in cancer of the esophagus. The integration of molecular markers of exposure, biological effect and individual susceptibility into epidemiological studies can contribute to strengthening the causal link between exposure and disease and thus help assess the relative contribution of multiple risk factors to the aetiology of a specific cancer. For some genotoxic carcinogens the sequence of events leading to tumour formation is well understood from exposure, to metabolism and ultimately to specific mutations in transformation-associated genes. The mechanisms of action of carcinogens which do not interact directly with DNA but exert adverse effects through receptor-mediated modulation of intercellular signal pathways is far less well understood and an example of this is the interaction between diet and hormones. Furthermore, there is increasing awareness that individual response to environmental agents may depend to a significant extent on the genetic background of the individual or population. This has long been known from animal experiments but human cancer susceptibility is a complex genetic trait involving genes responsible for carcinogen metabolism, DNA repair and as yet unidentified cell specific susceptibility genes. Phenotypic changes observed during tumour progression reflect the sequential acquisition of genetic alterations. To assess the contribution of mutations in the various genes involved in the carcinogenic process may require their expression in transgenic animals or knock out mice. This has again placed animal experimentation into the forefront of mainstream cancer research.