Cellular epigenetics: effects of passage history on competence of cells for "spontaneous" transformation.

"Spontaneous" neoplastic transformation of cells in culture has been shown to be an adaptive response to moderate physiological constraints such as contact inhibition and lowered concentrations of serum. These are the same constraints that promote normal differentiation of a variety of cell types. Because both normal and neoplastic development represent enduring changes in response to constraint, spontaneous transformation can be considered a form of epigenesis. This phenomenon permits the use of established cell lines in developing general epigenetic principles with all of the advantages of manipulation, efficient cloning, and quantification afforded by such systems. Being environmentally sensitive, however, the responsive capacity of cell lines is subject to fluctuation and long-term modification. I therefore set out to define the conditions used in maintaining cells that influence their competence to undergo transformation with the aim of controlling that competence. It proved to be sensitive to both the population density and frequency of three different repetitive passage regimens. Both the saturation density of the cells and their capacity to produce transformed foci varied initially in different ways within the same regimen in two consecutive passage series starting from the same frozen stock, but both parameters eventually settled down to values characteristic of each of the three regimens. As a result, three sublines were developed of high, intermediate, and low competence for transformation. Each of the sublines has special advantages for studying different aspects of epigenetic change. In the process of developing the sublines, a number of observations were made that reinforce the epigenetic nature of neoplastic transformation and are consistent with the concept of progressive state selection as the basis of the change. That concept can be considered a first step in the formal analysis of epigenesis.