Carcinogenesis; a comprehensive survey最新文献

Advances in the methodology to culture normal human lung cells have provided opportunities to investigate fundamental problems in biomedical research, including the mechanism(s) of carcinogenesis. Using the strategy schematically shown in Figure 1, we have initiated studies of the effects of carcinogens on the normal progenitor cells of the human cancers caused by these carcinogens. Extended lifespans and aneuploidy were found after exposure of mesothelial cells to asbestos and bronchial epithelial cells to nickel sulfate. These abnormal cells may be considered to be preneoplastic and at an intermediate position in the multistage process of carcinogenesis. Human bronchial epithelial cells can also be employed to investigate the role of specific oncogenes in carcinogenesis and tumor progression. Using the protoplast fusion method for high frequency gene transfection, vHa-ras oncogene initiates a cascade of events in the normal human bronchial cells leading to their apparent immortality, aneuploidy, and tumorigenicity in athymic nude mice. These results suggest that oncogenes may play an important role in human carcinogenesis.

Diploid Syrian hamster embryo cells are particularly appropriate for the study of the transformation phenomenon in target cells. In vitro morphologic transformation occurs in a dose-dependent manner and is characterized by random crisscrossing and piling of cells; it correlates with tumorigenicity because individually transformed cell colonies can be isolated, cell lines can be developed, and the formation of tumors can be demonstrated after the injection of the transformed cells into either Syrian hamsters or athymic nude mice. HEC can also be used to investigate stages of carcinogenesis, initiation, and promotion. The susceptibility of normal HEC to transformation by environmental carcinogens including asbestos, bisulfite, nitrated non-carcinogenic polycyclic hydrocarbons, and X- or ultraviolet irradiation has made possible the determination of a variety of cell responses as they proceed to the neoplastic state. The initiation is usually a hereditary process involving single-hit kinetics and the transformation data indicate there is no measurable threshold response to carcinogens. The promotional aspects of transformation are readily modulated by environmental factors and have a threshold, as well as a maximal effect. The results of transformation studies using hamster cells indicate that in vitro studies are relevant to carcinogenesis and indicate that the various steps involved can be identified. Therefore, it should be possible to intervene with the various stages or steps leading to neoplasia so that cancer can be prevented.

Ionizing radiation is carcinogenic to many, if not most, tissues. Its carcinogenicity varies, however, depending on the tissue exposed, conditions of exposure, genetic background, sex, age of the exposed individual, and other factors. The neoplasms induced by radiation also vary in their types and in their times of onset, depending on the age and sex of the exposed individual. The long induction period for radiation carcinogenesis and the enhancing or inhibiting effects of other agents acting after irradiation imply that the induction of cancer is a multistage process, in keeping with experiments on radiation-induced cell transformation in vitro. The molecular nature of the steps involved in radiation carcinogenesis remains to be fully elucidated, but it is being rapidly explored through advances in somatic cell genetics and molecular biology. The resulting insights will significantly extend epidemiological data in future attempts to estimate the carcinogenic risks of low-level radiation.