Is There a Critical Target Gene for the First Step in Carcinogenesis?

Ann R. Kennedy
1991 Environmental Health Perspectives  
Our work has suggested that a high-frequency event is involved in the initiation phase of malignant transformation in vitro; a later, mutationlike event appears to be involved in the later stages of transformation. There may be no specific "target gene" which directly interacts with carcinogens. It is hypothesized that nonspecific types of DNA damage are involved in the induction of an ongoing process we know as carcinogenesis. Several genes could be involved in maintaining this process. Our
more » ... ent results suggest that c-myc and c-fos could be involved in the early stages of carcinogenesis, as they are affected by anticarcinogenic protease inhibitors in a manner that corresponds to the way in which protease inhibitors suppress malignant transformation. Nature of the Initiating Event in Carcinogenesis Our previous work has suggested that a high-frequency event is involved in the induction of radiationinduced transformation in vitro (1-8). The work of several other investigators has now suggested that a similar high-frequency initiating event occurs in carcinogenesis in both in vitro and in vivo systems, with many different types of DNA-damaging agents initiating the carcinogenic process, as has been reviewed elsewhere (7-11). Given the high-frequency nature of the initiating event in carcinogenesis, it is unlikely to be a specific locus mutation, as studies of mutation frequencies have shown them to occur at orders of magnitude below those observed for malignant transformation. The initiating event does not behave like a mutation, as it appears to be a reversible phenomenon. We have observed that certain protease inhibitors, which are highly effective in their ability to suppress malignant transformation in vitro (12) and in vivo (13), are capable of reversing initiation (14). There is much evidence from in vivo studies that lesions thought to represent "initiated" or "premalignant" cells are capable ofreverting to their normal state. For example, Terzaghi-Howe (15) observed that contact with normal tracheal epithelium could revert initiated "pre-neoplastic" tracheal epithelial cells to a normal condition. It is well known that "premalignant" lesions in vivo, such as squamous metaplasia, dysplasia, etc., are readily reversible in nature.
doi:10.2307/3431189 fatcat:s3luqzdgnzak7owusa2tpksrsm