Figure 2. Sources of heterogeneity among cancers.

Differences in the cell-of-origin can directly and indirectly influence the phenotype of tumorigenic cells and, perhaps, whether or not the cancer is hierarchically organized. A) Different cell types in a stem/progenitor cell hierarchy within a normal tissue may be transformed into cancer cells. The properties of the cell-of-origin influence the types of mutations that are competent to transform and the properties of the resulting cancer (Huntly et al., 2004; Wang et al., 2010). (B) Spatial differences in the identity of the cell-of-origin within tissues influence the types of mutations that are competent to transform and the properties of the resulting cancer (Gibson et al., 2010; Johnson et al., 2010). (C) Temporal differences in the cell-of-origin also influence the types of mutations that are competent to transform and the properties of the resulting cancer (Magee and Morrison, unpublished data), consistent with the observation that the driver mutation spectrum changes with age in patients (Downing and Shannon, 2002)(see text for references regarding age-related changes in the incidence of specific mutations).