Growth fraction as the major determinant of multicellular tumor spheroid growth rates

Multicellular tumor spheroids (MTS) from seven murine solid tumors have been compared in terms of their growth rate and the fraction of the cells that are in cycle. Growth rates ranged from a low of 19 micron/day through a maximum of 106 micron/day, demonstrating a far wider range of growth rates than is observed when the same tumors are grown as monolayers. Through the use of an [125I]iodouridine deoxyribose incorporation assay, it has been possible to demonstrate that cells within the MTS that are in cycle double at a slower rate than they do in monolayers and that the depth of the dividing shell ranges from less than 20 to more than 100 micron. The depth of the dividing shell or the growth fraction is highly correlated with the MTS growth rate (r = 0.97). We conclude that the major factor that determines the wide range of MTS growth rates, in spite of relatively uniform doubling times in monolayer, is the fraction of the cells that are in cycle.