FIGURE 2.

Theoretical tumor growth module: a cord-finger structure. In a tumor growth module, it is possible to distinguish: (A) An internal hypoxic zone (pink color) where quiescent CSC₃s lie, generated at later divisions and migrating externally in spatially coordinated patterns, toward the tumor/host interface, endowed with more favorable stereo-trophic conditions, thus creating an invasive front. Here, they could install in metastatic niches as dormant CSC₃s by EMT environmental signals (WNT, TGFb) and eventually revert to self-renewing CSC₁s by MET signals (BMP, LIF). (B) An external normoxic zone (light-blue color), where CSC₃s lie, generated at earlier divisions and thus more proximal to the tumor/host interface, where favorable micro-environmental conditions (space, oxygen, nutrients, pH) exist. Here, these cells could undergo EMT/MET switch, subsequent asymmetric division and differentiation in CPCs and then in CDCs, thus generating a growth module with a defined cell hierarchy, responsible for a peripheral finger-like morphology (violet broken lines). With regards to the CDCs, the question arises of whether or not they are still proliferating.