The significance of biological heterogeneity.

Heterogeneity of expression for a variety of characteristics is found among malignant cells in the organism and in culture. Normal cells are relatively uniform when organized in a tissue, but become heterogeneous for many characteristics when they are dispersed and grown in monolayer culture. The heterogenizing effect of growth in culture indicates that the morphology and behavior of normal cells is ordered by their topological relations in tissues and other homeostatic influences of the organism. Weakening of these ordering relations may contribute to malignant transformation, as it usually does in rodent cell culture. Although phenotypic differences among cells of a given type may be transient, they can be perpetuated by protracted exposure to selective conditions. Examples are cited of selection which leads to an adapted state that is heritable for many cell generations after removal of the selective conditions. Such heritable adaptations are analogous to the Dauermodifikationen, or lingering changes, first described in ciliated protozoa and shown there to be under cytoplasmic control. The concept of progressive state selection is introduced to account for heritable adaptation at the cellular level. It depends on the spontaneous occurrence of transient, variant states and their successive selection to progressively higher levels of adaptation to an altered microenvironment. Although the process is basically epigenetic, it may be stabilized by genetic change. The concept is consistent with our present knowledge of tumor development, including progression to metastasis, and with epigenetic aspects of normal development.