Fig. 1. The two main working models describing the generation of tumor heterogeneity. (A) The `cancer stem cell' model. Accumulation of genetic mutations in stem cells might lead to the formation of cancer cells with self-renewal properties (cancer stem cells). These cancer stem cells drive tumor progression and heterogeneity by proliferating and generating some differentiated cancer cells. (B) The `clonal evolution' model. In this model, epigenetic and genetic events can induce the transformation, dedifferentiation and acquisition of self-renewal properties in any cell type. The evolution of cancer cells that derive from the original cell is unstable, and depends on the surrounding environment and on paracrine signals that come either from stroma cells (green arrows) or from other tumor cells (brown arrows). The two models are not necessarily mutually exclusive.