Figure 10

Acquired chemoresistance towards metronomic CPA therapy – a hypothetical model of the equilibrium between stem cells and endothelial like cells in HUH-REISO. During therapeutic pressure tumor cells acquire stepwise pluripotency. Reprogramming is associated with regulations of the Notch-pathway (Notch-1), resulting in enrichment of cells with increased expression levels of Thy-1, Oct-4, Sox-2 and Nanog. This pool of cells is the basis for increased adaptiveness of the tumor to therapy effects as hypoxia. Differentiation to a functional endothelial like phenotype, connected with tissue reorganization, counteracts antiangiogenic therapy. Finally, in the chemoresistant tumors an equilibrium between differentiation and self-renewal exists. In contrast to chemoresistant tumors, induction of Notch-3 expression in chemosensitive tumors leads to the induction of a differentiation process, which nearly flushes out the whole pool of pluripotent tumor cells.