Differentiation of Cancer Stem Cells

Abstract

Tumors originally develop from normal cells that acquire the ability to grow aberrantly and metastasize to distant organs (Hanahan and Weinberg, 2000). These malignant transformations are considered to be induced by the accumulation of multiple genetic/epigenetic changes (Yamashita et al., 2008b). Although considered monoclonal in origin, cancer is composed of heterogeneous cell populations. This heterogeneity is traditionally explained by the clonal evolution of cancer cells through a series of stochastic genetic events (clonal evolution model) (Fialkow, 1976; Nowell, 1976). In contrast, cancer cells and stem cells have similar capabilities with respect to self-renewal, limitless division, and the generation of heterogeneous cell populations. Recent evidence suggests that tumor cells possess stem cell features (cancer stem cells) to self-renew and give rise to relatively differentiated cells through asymmetric division, thereby forming heterogeneous populations (cancer stem cell model) (Clarke et al., 2006; Jordan et al., 2006). Accumulating evidence supports the notion that cancer stem cells can generate tumors more efficiently in immunodeficient mice than non-cancer stem cells in hematological malignancies and in various solid tumors (Al-Hajj et al., 2003; Bonnet and Dick, 1997; O'Brien et al., 2007; RicciVitiani et al., 2007; Singh et al., 2004). Cancer stem cells are considered to be resistant to chemotherapy and radiotherapy, which might be associated with the recurrence of the tumor after treatment (Boman and Huang, 2008; Dean et al., 2005; Diehn et al., 2009; Zou, 2008). These findings have led to the proposal of “destemming” cancer stem cells (Hill and Perris, 2007) in order to induce their differentiation into non-cancer stem cells or to eradicate cancer stem cells by inhibiting the signaling pathways responsible for their self-renewal. Recent studies have supported this proposal and suggest the utility of several factors to induce the differentiation of cancer stem cells and facilitate tumor eradication; however, it is still debatable whether the simple differentiation of cancer stem cells effectively eradicates tumors. Here, we summarize current knowledge on the differentiation of cancer stem cells and discuss the utility and limitation of differentiation therapy to eliminate cancer.