Clonal heterogeneity in populations of normal cells and tumor cells

Abstract

A review of published literature indicates that heterogeneity within populations of mammalian cells has been repeatedly observed and frequently modeled. However, heterogeneity is not well enough understood to ameliorate its consequences in populations of tumor cells. Our own experimental observations, using time lapse photogeaphy, indicate that when murine erythroleukemia cells are induced to terminally differentiate the distribution of life times of unrelated cells becomes more heterogeneous and that of sister cells become more similar. Time lapse photography of NIH3T3 murine fibroblasts reveals that the human ras oncogene decreases the similarity of life times of sister cells and increases the similarity of mother-daughter cells. Observations of colony sizes also detect heterogeneity heterogeneity of cell life times within a population. Inspite of this heterogeneity, cell growth rates apparently persist when primary colonies are recloned and allowed to form secondary colonies since the sizes of secondary colonies resemble each other and the primary colony from which they were derived. The ras oncogene weakens the persistence of cell growth rates since it increases the variance of sizes between related secondary colonies. These observations have led to the development of a new divided-colony assay for detecting the response of heterogeneous tumor cell populations to chemotherapeutic drugs in vitro. In order to better understand observations of clonal heterogeneity a growth rate diffusion model is outlined. In this model the growth rate of daughter cells takes a random walk away from the growth rate of mother cells. Criteria are suggested for evaluating this model, and other models for describing heterogeneity within proliferating populations. Several open questions are presented concerning our understanding of clonal heterogeneity of normal and tumor cells.