potential for initiating tumor growth. (Fig. 4). These two models are not mutually exclusive, as CSCs themselves undergo clonal evolution. Thus, the secondary more dominant CSCs may emerge, if a mutation confers more aggressive properties (Fig. 5). Tying CSC and stochastic models together A study in 2014 argues the gap between these two controversial models can be bridged by providing an alternative explanation of tumor heterogeneity. They demonstrate a model that includes aspects of both the Stochastic and CSC models. They examined cancer stem cell plasticity in which cancer stem cells can transition between non-cancer stem cells (Non-CSC) and CSC via in situ supporting a more Stochastic model. But the existence of both biologically distinct non-CSC and CSC populations supports a more CSC model, proposing that both models may play a vital role in tumor heterogeneity. The cancer stem cell immunology model This model suggests that immunological properties may be important for understanding tumorigenesis and heterogeneity. As such, CSCs can be very rare in some tumors, but some researchers found that a large proportion of tumor cells can initiate tumors if transplanted into severely immunocompromised mice, and thus questioned the relevance of rare CSCs. However, both stem cells and CSCs possess unique immunological properties which render them highly resistant towards immunosurveillance. Thus, only CSCs may be able to seed tumors in patients with functional immunosurveillance, and immune privilege may be a key criterion for identifying CSCs. Furthermore, the model suggests that CSCs may initially be dependent on stem cell niches, and CSCs may function there as a reservoir in which mutations can accumulate over decades unrestricted by the immune system. Clinically overt tumors may grow if: A) CSCs lose their dependence on niche factors (less differentiated tumors), B) their offspring of highly proliferative, yet initially immunogenic normal tumor cells evolve means to escape immunosurveillance or C) the immune system may lose its tumorsuppressive capacity, e.g. due to ageing. Debate The existence of CSCs is under debate, because many studies found no cells with their specific characteristics. Cancer cells must be capable of continuous proliferation and self-renewal to retain the many mutations required for carcinogenesis and to sustain the growth of a tumor, since differentiated cells (constrained by the Hayflick Limit) cannot divide indefinitely. For therapeutic consideration, if most tumor cells are endowed with stem cell properties, targeting tumor size directly is a valid strategy. If CSCs are a small minority,