Carcinogenesis; a comprehensive survey最新文献

This review has provided an update on current progress in identifying recurring sites of chromosome change in human malignant melanoma. Despite methodologic difficulties, a recurring and decidedly nonrandom pattern of chromosome change is beginning to emerge for this neoplasia. It appears most reasonable to suggest that as an increasing number of cases of melanoma are cytogenetically examined, the stratification of patients into defined subgroups based upon specific chromosome abnormalities will be possible. At present, the clinical utility of chromosome analysis in malignant melanoma is indeterminate. However, the pinpointing of regions of the genome which are characteristically altered in this tumor may be of significant benefit in targeting future molecular (and hopefully mechanistic) investigations. Continued study of the basic genetics of malignant melanoma would appear a particularly fruitful avenue to continue and it assuredly will add to our understanding of the causation, progression, and ultimately the control of this disorder.

The propagation of pigmented cells derived from normal skin, common and precursor nevi, and primary and metastatic melanoma in tissue culture has allowed the study of tumor progression under experimental conditions. In accordance with Clark's hypothesis, which is based on histopathological observations, cells isolated from different stages of tumor progression show a stepwise development of a malignant phenotype as defined by different biological parameters: life span in culture, anchorage-independent growth, increased growth autonomy from exogenous growth factors, expression of melanoma-associated antigens, progressively severe chromosomal abnormalities, and tumorigenicity in nude mice. Qualitative and quantitative differences exist between normal melanocytes and nevus cells on the one hand, and between VGP primary and metastatic melanoma cells on the other. Little information, however, is available on cells from dysplastic nevi and RGP primary melanoma cells. Preliminary results suggest that the biologic, immunologic and genetic characterization of these cells from the intermediate stages of tumor development will significantly increase our understanding of the pathogenesis of melanoma.

Inbred mouse strains that differing widely in their susceptibility to multistage skin carcinogenesis provide useful models for studying the genetic factors involved and advancing our understanding of the biochemical and molecular events associated with this process. The process of skin tumor initiation appears to be somewhat similar in various strains of mice, and most data in the literature suggest that differences in response to skin tumor promoters are a major determinant in controlling susceptibility to multistage skin carcinogenesis. A model system has been developed for examining the genetics of susceptibility to skin tumor promotion. The susceptibility to phorbol ester skin tumor promotion in crosses between DBA/2 and C57BL/6 mice is inherited as an incomplete dominant trait, and neither X-chromosome nor cytoplasmic genetic determinants appear to play a major role in determining susceptibility in these two inbred strains. In addition, two or more genetic loci contribute to the higher sensitivity of DBA/2 mice than C57BL/6 mice to TPA-induced skin tumor promotion. Further studies to characterize these genes will contribute greatly to our understanding of the mechanisms of phorbol ester skin tumor promotion. In addition, much work should now be directed at understanding the cellular, biochemical, and molecular mechanisms for differential responsiveness not only to phorbol esters but also to other classes of tumor promoters.