Ordered heterogeneity and its decline in cancer and aging.

Ordered heterogeneity was introduced as a basic feature of the living state in the mid-1950s. It was later expanded to "order in the large over heterogeneity in the small" as the first principle of a theory of organisms. Several examples of ordered heterogeneity were given at the time to illustrate the principle, but many more have become apparent since then to confirm its generality. They include minimum size requirements for progressive embryological development, the errant behavior of cells liberated from tissue architecture, their sorting out to reconstitute tissues on reaggregation, and contact regulation of cell proliferation. There is increasing heterogeneity of cell growth with age, and marked heterogeneity of many characters among cells of solid epithelial tumors. Normal growth behavior is reintroduced in solitary, carcinogen-initiated epidermal cells by contact with an excess of normal epidermal cells. Contact normalization also occurs when solitary hepatocarcinoma cells are transplanted into the parenchyma of normal liver of young, but not of old, animals. The role of the plasma membrane and adhesion molecules in ordering heterogeneity is evaluated. Organizing the results in a conceptual structure helps to understand classical observations of tumor biology such as the lifetime quiescence of carcinogen-initiated epidermal cells and the marked increase of cancer incidence with age. The principle of order above heterogeneity thus provides a unifying framework for a variety of seemingly unrelated processes in normal and neoplastic development. Whereas contact between cells is required for these processes to occur, gap junctional communication is not required.