Generation of intercellular heterogeneity of growth and function in cloned rat thyroid cells (FRTL-5).

The most characteristic hallmarks of human nodular goiters are nodular growth and heterogeneity of structure and function between different areas of the same goiter. In search of the earliest detectable stage of thyroid heterogeneity we have observed doubling times, TSH dependency, and thyroglobulin production in colonies formed from individual FRTL-5 cells growing as monolayers in slide flasks. Single cells and the colonies derived thereof were followed on photographs taken daily until confluence. We observed that each cell had its individual stable multiplication rate throughout the observation period. This was true for all TSH doses tested (0.625-10 mU/ml). A wide range of doubling times (20 h to almost infinite) in the individual cells was observed. The mean growth velocity of subcloned cell lines was highly reproducible in consecutive passages, although a minority of cells escaped this rule. Cells with either high or low thyroglobulin content occurred in clusters, indicating again that specific traits tend to remain stable in the offspring. We conclude that a highly individual growth program, unrelated to mutation, appears to be switched on at the very moment a cell is generated and that this program is passed on to the majority of the offspring, with a minority of cells acquiring qualities differing from those of their sister cell. Therefore, goiter heterogeneity may be the in vivo amplification of a natural phenomenon occurring in all growing cells. Monoclonal adenomas in vivo and nontransformed immortal cell lines in vitro may represent the far end of the large spectrum of individual growth potency among normal thyrocytes.