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Three-Dimensional In Vitro Models in Glioma Research - Focus on Spheroids

In the field of glioma research, in vitro models are widely used to investigate tumor biology as well as tumor response to chemotherapy and radiation. There is an increasing need to improve these in vitro models in order to meet the new challenges arising in drug discovery. It is thus important that development of new drugs is based on the latest knowledge about glioma biology such as for example the recent discovery of tumor stem cells (Reya et al., 2001). When investigating glioblastomas in vitro – and especially the supposed tumor stem cells – three dimensional multicellular spheroid models have recently come into focus. The aim of this chapter is to review the development as well as the most recent aspects of the three-dimensional glioma in vitro models focusing on glioma spheroids. The implementation of these models in current and in future in vitro glioma research will be discussed putting emphasis on the themes described below. Cell lines cultured as monolayers have been the in vitro model of choice for many years (Ponten & Macintyre, 1968). However, the three-dimensional aspect came into focus in the 1970’s, where scientists started to grow tumor cells from cell lines as multicellular spheroids (Yuhas et al., 1977). Over the years the spheroid model has been improved by deriving spheroids from cells obtained from dissociated primary glioblastoma tissue (Mackillop et al., 1985) as well as by using organotypic primary spheroids derived from small tumor fragments (Bjerkvig et al., 1990). In general, most in vitro studies are performed with cells cultured in conventional serumcontaining medium. Recently – as the tumor stem cell theory has evolved – the culturing medium has come into focus. It has thus been demonstrated that the use of serum-free medium for culturing of cell line-derived spheroids preserved the in vivo-like features as well as the tumor stem cell-like phenotype suggesting crucial importance of the use of serum-free medium in tumor stem cell research (Lee et al., 2006). Identification of the glioma stem cells is still a matter of discussion. The most used marker in the field has been the cell surface marker CD133. Expression of this putative tumor stem cell marker in gliomas has been studied in several papers demonstrating clusters or niches of CD133 positive tumor cells as well as CD133 positive single cells dispersed in the tumor