Figure 1.

Modeling cellular heterogeneity of cancer. (A) The stochastic model assumes that cancer cell phenotypes are primarily defined by intrinsic factors, in particular driver mutations. It indicates a clonal evolution of cancer. However, this model may not adequately address phenotypic variations within individual clones; (B) The cancer stem cell model assumes that cancer is organized in a hierarchical structure that, at least in part, resembles that of the tissue of origin. Tumorigenic potential is limited to the cancer stem cell subpopulation. In addition, cellular heterogeneity of the cancer is a product of multipotent cancer stem cells. However, the maintenance of coexisting genetically distinct clones in most late-stage cancers has not been adequately addressed by this model; (C) Emerging evidence suggests a combination of these two models in which cancers are driven by one or multiple dominating clones, some of which may be organized in a hierarchical manner. However, at the time of diagnosis, the original hierarchy may be altered due to acquisition of genetic or epigenetic events that promote tumorigenic capacity and impair differentiation.