SELF-REGULATION OF GROWTH IN THREE DIMENSIONS

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Abstract
Multi-cell spheroids were grown in soft agar. When each spheroid was cultured in a large volume of medium, frequently renewed, all spheroids eventually reached a dormant phase at a diameter of approximately 3–4 mm and a population of approximately 106 cells. In the dormant spheroid, newly generated cells at the periphery balanced those lost by necrosis in the center. We propose that this dormant phase is due to a gradual reduction in the ratio of surface area to volume: a size is achieved beyond which there is insufficient surface area for the spheroid to eliminate catabolites and absorb nutrients. Thus, in the face of unlimited space and of new medium, three-dimensional cell populations become self-regulating. This phenomenon contrasts with standard tissue culture in which cell populations, living on a flat plane in two dimensions, will not stop growing in the face of unlimited space and new medium because the ratio of surface area to volume remains constant.