Tumor cell instability, diversification, and progression to the metastatic phenotype: from oncogene to oncofetal...

It is proposed that tumor cell instability and the expression of cellular diversification mechanisms ensure that malignant neoplasms contain heterogeneous, phenotypically diverse tumor cell subpopulations. In such potentially unstable cellular mixtures of tumor cell phenotypes, some malignant cells may ultimately evolve with the most favorable properties for their progression to metastatic cells. Rates of cellular phenotypic instability and phenotypic diversification as well as their underlying causes appear to vary greatly among different tumor cells, and they are probably modulated by further genetic and chromosome changes and more frequently by intra- and extracellular epigenetic events that also differ, depending on the nature of the tumor cells and their cellular and microenvironmental interactions. Diversified malignant cells are characterized by quantitative and perhaps a few qualitative differences in gene expression, which may explain their abilities to undergo rapid changes in phenotypic properties. As tumor diversification and selection proceed uniquely in vivo, highly malignant cell subpopulations may eventually become dominant and gradually and independently lose their cellular and microenvironmental responsiveness. Tumor cell diversification mechanisms may be similar or identical to normal developmentally regulated diversification mechanisms that are used during embryonic and postembryonic cell diversification and development.