Figure 3

Putative algorithm for tumor self-assembly and possible clinical interventions according to the functional compartment model: Depicted is a schematic illustration of two colonies (blue circles) within a solid tumor (green box). At each cell division a TSC (blue) has to decide whether it will divide symmetrically (a1) or asymmetrically (a2). The resulting non-TSC from decision a2 has in turn the options to differentiate early (b1) and may thus gain functions like the production of growth factors and cytokines (e.g. VEGF) that potentially support the colony or to divide as a transitory amplifying cell several times (b2). In the latter scenario the non-TSC will differentiate and gain growth-supporting functions at a later time point (b3+b4). This theoretical model implies possible anti-cancer interventions: drugs that would specifically inhibit the TSC decision at point a1 or a2, such as "epigenetic therapeutics" [105], would obviously prevent outgrowth of a tumor. Conventional chemotherapy mostly affects fast proliferating cells (b2), but hardly targets slow-proliferating TSC and differentiated non-TSC [25]. Another option would be drugs that specifically inhibit the early differentiation (b1) or the function of already differentiated non-TSC (e.g. epigenetic [105] and/or antiangiogenic therapeutics [29, 105, 106]). Another approach is to drive non-TSC to terminal differentiation without any oncogenic function (b4), which is currently employed as a "differentiation therapy" in various cancers such as neuroblastoma and acute myeloid leukemia [107–109].