# Recent Advances in the Targeting of Head and Neck Cancer Stem Cells
## 2 Cancer Stem Cells  
### Evolution Model  
There are two models of tumorigenesis, known as the stochastic or clonal evolution model and the hierarchy or cancer stem cell (CSC) model, that currently predominate in describing the initiation, growth, progression, and heterogeneity of tumors [4; 5]. The clonal evolution model holds that a tumor consists of a heterogeneous population of cells, each possessing the equal probability to initiate, sustain, and promote tumor growth. In this model, a stochastic acquisition of various genetic and epigenetic changes through time confers a selective advantage to the fittest clones of tumor cells, allowing them to become more aggressive and expand while outcompeting clones with less fitness. However, clonal fitness tends to change spatially and temporally as requirements and conditions vary in different tumor regions over the course of the disease. For instance, hypoxic regions may select for more aggressive and resistant clones, while nutrient-rich regions may boost the rapid-growing clones [6; 7]. Furthermore, it was recently shown that mutations in certain genes such as DNA damage response genes may be preferentially selected upon exposure to radiation therapy [8].  
Contrary to this, the CSC model proposes that only a minority of cells within a tumor can drive tumor growth by differentiating into phenotypically diverse cells that comprise the bulk of cells in a tumor. This model assumes that tumor growth and progression follow a hierarchical structure reliant on differentiation capacity, where highly tumorigenic CSCs sustain the long-term maintenance of intermediate and terminally differentiated progenitors. Similar to normal stem cells, CSCs exhibit an unlimited self-renewal and regenerative capacity, allowing them to generate more stem cells (symmetric division) as well as give rise to functionally heterogeneous cancer cell lineages with a limited proliferative and tumorigenic capacity (asymmetric division). The hierarchy model was first recognized in hematopoietic malignancies [9; 10], and later on, a broad spectrum of specific cell surface markers allowed its identification in solid tumors [11].  
However, in the last decade, it became evident that the hierarchy model is more dynamic and complex than originally imagined. Thus, accumulating evidence suggests an alternative model of cellular plasticity which has partly reconciled both the CSC and clonal model by postulating that cancer cells possess a dynamic capacity for bidirectional interconversion between a stem cell and non-self-renewing/non-stem-like states. It is assumed that stemness and CSC plasticity are influenced by diverse microenvironmental stimuli and/or genetic tumor cell alterations that work simultaneously over time, allowing differentiated tumor cells to reacquire stem cell characteristics [12]. Moreover, the newest model of CSC-induced tumorigenesis (monophyletic model of cancer), which has been proposed very recently by [PERSON] and colleagues, suggests that CSCs are stem cells that evade control of differentiation whose primary purpose was to restore damaged tissues [13] (Figure 1). However, as this is a very recent model, it still needs more experimental evidence.