[Generalities about carcinogenesis].
Currently, carcinogenesis appears to be a process much more complex than what was believed a decade ago. The study of the genome of human tumour cells has revealed a number of genetic and epigenetic modifications much greater than suspected. Moreover, the delay between the first initiating event (when its timing is precisely known) and the clinical emergence of a cancer can be very long, up to 60 years. This long delay shows that risk factors during infancy and childhood deserve critical analysis. The epidemiological data emphasize the role of promotion. For example, alcohol, asbestos are not mutagenic, but cause irritation and cell proliferation. Even for tobacco, the role of promotion appears to be more important than that of mutations. In human carcinogenesis, initial mutations do not appear to be a limiting or crucial step. Finally, the biological study of carcinogenesis has shown that the initiating cell is not passively affected by the accumulation of damages by the carcinogenic physical or chemical agents. It reacts through at least three mechanisms: (a) by fighting against reactive oxygen species (ROS) generated by any oxidative stress, such as UV or ionizing radiations, (b) by eliminating injured cells (mutated or unstable), through two ways--(i) apoptosis, which can be initiated by doses as low as a few millisieverts, thus eliminating cells with genomes that have been damaged or ill-repaired, (ii) death of cells during mitosis when lesions have not been repaired--, (c) by stimulating or activating DNA repair systems. Furthermore, intercellular communication systems inform a cell about the presence of an insult in neighbouring cells. A system of intercellular induction of apoptosis exists whereby non-transformed cells can selectively remove transformed cells. Modern transcriptional analysis of cellular genes using microarray technology reveals that many genes are activated by doses of carcinogenic agents much lower than those for which mutagenesis is observed. These methods have been a source of considerable progress. Moreover, it was thought that carcinogenesis was initiated by lesions of the genome affecting at random a few specific targets (proto-oncogenes, suppressor genes, etc.). This relatively simple model has been replaced by a more complex one, in which the relationship between the initiated cells and their microenvironment plays an essential role. Thus, the carcinogenic process is counteracted by effective defence mechanisms in the cell, tissue and the organism. With regard to tissue, the mechanisms that govern embryogenesis and direct tissue repair after injury appear to play also an important role in the control of cell proliferation. This is particularly important when a transformed cell is surrounded by normal cells that appear to be able to inhibit its proliferation. Tissue disorganization by inflammation or by the death of a large proportion of cells is often associated with the escape of the initiated cells and the emergence of a clone of pre-neoplastic-neoplastic cells. The effectiveness of immunosurveillance is also shown by the large increase in the incidence of several types of cancers among immunodepressed people.
Tubiana
Maurice
M
Centre Antoine-Beclère, faculté de médecine, 45, rue des Saint-Pères, 75006 Paris, France. maurice.tubiana@biomedicale.univ-paris5.fr
D000428:Alcohol Drinking / Q000009:adverse effects; D017209:Apoptosis; D015197:Carcinogenicity Tests; D004260:DNA Repair; D006801:Humans; D009153:Mutagens / Q000633:toxicity; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D009857:Oncogenes; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species; D012307:Risk Factors; D014466:Ultraviolet Rays / Q000009:adverse effects
D009153:Mutagens; D017382:Reactive Oxygen Species