Models of tumor heterogeneity. Tumors are composed of phenotypically and functionally heterogeneous cells. There are 2 theories as to how this heterogeneity arises. According to the stochastic model, tumor cells are biologically equivalent, but their behavior is influenced by intrinsic and extrinsic factors and is therefore both variable and unpredictable. Thus, tumor-initiating activity cannot be enriched by sorting cells based on intrinsic characteristics. In contrast, the hierarchy model postulates the existence of biologically distinct classes of cells with differing functional abilities and behavior. Only a subset of cells can initiate tumor growth; these cancer stem cells possess self-renewal and give rise to nontumorigenic progeny that make up the bulk of the tumor. This model predicts that tumor-initiating cells can be identified and purified from the bulk nontumorigenic population based on intrinsic characteristics.