Different tumor models of GBM. According to the cancer stem cell model (left panel), a subpopulation of cancer cells possesses the capacity of self-renewal, clonal sphere formation and in vivo tumor formation, as well as the capability to form progeny with a more restricted fate (darker colors). This forms a hierarchical lineage system where the primary therapeutic cell target is the CSC itself. The clonal evolution model (middle panel) exhibits no lineage hierarchy, as the multiple cell populations are the result of different genetic mutations (broken arrows). There is no cell hierarchy, because most of these cell subtypes self-renew and are capable of tumor formation, which makes them all targets of therapeutic interventions. In a complex system (right panel), both genetic and epigenetic changes might occur within a single tumor, resulting in a multifaceted cell system where several tumor-initiating cell types may coexist. While genetic mutations may produce new tumor cell populations (#3), epigenetic changes (#2) might enable cells to produce progeny with a more or less restricted fate and also to temporarily adopt different states characterized by therapy resistance and expression of different cell markers. Another important feature of a complex system is that the individual cell populations interact (red arrows, #4). While all potential tumor forming cells have to be targeted for successful therapy in this model, the interruption of the cell-cell and cell-niche interactions may also weaken the tumor system as a whole. GBM, glioblastoma multiforme; CSC, cancer stem cell.