The stemness phenotype model proposes that all cancer cells have stem cell properties and that the stemness of individual cell depends on the microenvironment. (a) Cell division mode. (b) Schematic representation of the dynamic of cancer cells within a tumor. For simplicity, the depicted tumor is composed of three compartments (microenvironments M1, M2, and M3), and only three cell phenotypes are shown (non-CSC, intermediate, and CSC phenotype). According to the SPM, (1) all cancer cells (non-CSCs and CSCs) divide symmetrically, (2) changes in the microenvironment modify the phenotype of individual cells (e.g., broken arrows in M1→M2 or M2→M3, indicate phenotype transition and not cell division), thus, (3) non-CSCs are able to generate CSCs when changes in the microenvironment favours this conversion (e.g., from M1→M2→M3), (4) isolated single cells can generate a tumor (or a cell culture) containing different cell phenotypes. For instance, if a single cell (e.g., or CellB) is transferred alone to a microenvironment that allows its survival (e.g., M2) this cell has the potential, by only symmetrical division, to generate cells with intermediate phenotype as wells as cells with stem cell phenotype (clonal origin of tumors and cell lines). The same can be predicted for other cells regardless of their phenotype (e.g., CellC–CellG), and (5) the model predicts that the relative percentage of CSCs in a given tumor will depend on the microenvironmental profile of each individual tumor (e.g., expanding the size of the M3 compartment will result in an increase number of cells having a pure CSC phenotype). In this figure non-CSC (especially in Figure 1(b)) refers to any cancer cell that does not show any trait of stemness and not to a normal nontransformed cell.
