Fig. 1

Two Models for EMT Tumor Cells Giving Rise to CSCs. a. Branching Model. In this model EMT tumor cells give rise to the cycling CSC compartment in response to paracrine factors within a niche in the TME that is conducive to the development of this CSC subpopulation. Alternatively, EMT tumor cells give rise to the non-cycling, autophagic CSC compartment in response to stress conditions such as nutrient shortage, mechanical stress, hypoxia etc. It is possible that this is a default pathway occurring in the absence of paracrine factors. b. Hierarchical Model. Here, EMT tumor cells are induced to become autophagic CSCs in response to stress conditions in the TME. Once these stimuli are relieved and replaced or complemented by paracrine factors, autophagic CSCs become cycling CSCs that self-renew and replenish the pool of differentiated tumor cells. CSC, cancer stem-like cell; EMT, epithelial-mesenchymal transition; TME, tumor microenvironment