Fig. 1

Hypothetical model for a CSCN compartment for CSC development. Due to oxygen and nutrient deprivation in a centralized localization of the tumor, starving tumor cells shift energy metabolism to enhanced anaerobic glycolysis with lactate accumulation and release whereby some tumor cells exhibit autophagy or undergo necroptosis by production of DAMPs. Interaction of DAMPs with adjacent tumor cells at oxygen-deprived hypoxic conditions and lactate-mediated low pH can induce retrodifferentiation and CSC development. Recruitment and activation of immune cells by DAMPs and the cytokine-mediated inflammatory environment is altered by immune-modulatory activities of cytokines-, chemokines- and exosomes-releasing MSC also accumulating at the inflammatory sites of the tumor. Release of mediators and exosomes by both, tumor cells and MSC can also mutually alter functionality of both cell types and induce CSC generation. Furthermore, MSC directly interact with tumor cells by various different mechanisms whereby close interactions at certain conditions result in entosis or hybrid cell formation via MSC – tumor cell fusion. Both mechanisms develop different kinds of hybrid cells which exhibit divergent functionalities during further tumor development. Subsequent selection processes of hybrid cells after MSC – tumor cell fusion contribute to CSC development. CSCs in perivascular regions can be kept in a dormant/quiescent state before cytokine/growth factor stimulation can activate re-entry into the proliferative cell cycle and self-renewal