Tumor progression: potential role of unstable genomic changes.

It is generally accepted that the genome of tumor cells is less stable than that of most normal cells, and it has been hypothesized that this genomic instability is probably involved in the process of tumor progression. However, the rate of occurrence of classical spontaneous mutations in tumor cells is too low to account for the rapid changes that can occur during tumor progression. Thus it is likely that other types of changes, such as gene amplification, must be involved in tumor progression. Gene amplification has been extensively studied in relation to the development of drug resistance. Low levels of amplification can occur spontaneously in tumor cell populations, but the amplified genes are lost rapidly unless prolonged selective pressure is applied. This paper argues that unstable increases in the expression of genes, probably as a result of low levels of amplification, may be all that is required for some of the stages in the process of tumor progression. This may be particularly true for the steps involved in metastasis formation. Recent studies have suggested that microenvironmental conditions known to occur in tumors (hypoxia, nutrient deprivation) may induce gene amplification in cells. This suggests the possibility that such conditions could promote tumor progression.