Multicellular tumor spheroids: intermediates between monolayer culture and in vivo tumor

Pioneered by the work of two developmental biologists, J. Holtfreter and A. Moscona, in the 1940s and 1950s, the methodology of cell aggregates was adapted to cancer research by Sutherland and coworkers in 1971. Their aim was to develop a realistic and suitable in vitro model of tumor growth to be applied in radiobiology. Since then, the spectrum of research on multicellular tumor spheroids (MCTS) has rapidly increased and expanded to other areas of biomedical research and basic cell biology. However, therapeutically oriented investigations became the major domain of research with MCTS for many years. MCTS have not only considerably increased our knowledge of the radiation response of mammalian cells—the elucidation of the phenomenon of the cell–cell contact effect is to be emphasized—but they have also been applied to evaluate the role of microenvironmental factors and other epigenetic variables in controlling radiation survival, DNA repair processes, and the recruitment of quiescent cells in radiation therapy (for review, see Freyer, 1992). In addition, they have contributed to the understanding of cell response to various chemotherapeutic treatment modalities (for reviews, see Mueller-Klieser, 1987, 1997; Kunz-Schughart et al., 1998). Although the attempt to initiate routinely spheroid growth directly from patient L. A. Kunz-Schughart Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany