Fig. 2. Models of tumor heterogeneity.

The clonal evolution theory was the first model to describe a way in which cancer cells with diverse phenotypes could arise within a tumor. In this model, distinct cancer cell populations evolve progressively during multistep tumorigenesis due to heritable genetic and epigenetic changes. These stochastic events create the raw material for the selection and clonal outgrowth of novel cell populations arising from the acquisition of accumulating mutations. A second model is described by the classical CSC theory, which proposes that tumor heterogeneity arises when cancer cells within a given tumor reside in different states of stemness or differentiation. Critical to this model is the notion that CSC-to–non-CSC conversion is a unidirectional process. The plastic cancer stem cell theory describes a third and evolving model in which bidirectional conversions exist between non-CSCs and CSCs. This model implies that non-CSCs can continually create CSC populations throughout tumorigenesis.