Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)
Part II. Cancer stem cells
With so many markers for CRCSCs, distinct CRCSC populations can arise according to the combination of markers being expressed (Vermeulen et al., 2008; Kreso et al., 2014). Among ISCs, functionally distinct quiescent Bmi1-expressing and rapidly cycling Lgr5 expressing populations have been identified. Bmi1-expressing cells can give rise to Lgr5-expressing cells, indicating a hierarchy within the ISC population (Tian et al., 2011; Yan et al., 2012). However, another study shows bidirectional interconversion between slow and rapid-cycling ISC populations, with both populations showing properties of self-renewal and multipotency (Takeda et al., 2011). Within the CRCSC population, various combinations of markers, such as CD44, CD133, CD26 and CD166, give rise to populations that differ in their tumour initiation and growth abilities (Dalerba et al., 2007; Pang et al., 2010). Targeting one marker of self-renewal, such as Bmi1, does not change CD133 or CD44 expression (Kreso et al., 2014). Another study has identified three distinct functional subtypes within CRCSCs. The first subtype is involved in primary tumour growth; the second has long-term self-renewal potential and is important for tumour initiation, growth and metastases; and the third evolves only upon serial passaging (Dieter et al., 2011). The resulting marker-based and functional heterogeneity within the CRCSC population has potential implications for therapeutic targeting of CRCSCs.
Differentiated somatic cells can be reprogrammed to form induced pluripotent stem cells using a specific set of oncogenic reprogramming factors, such as Sox2, Oct4, Nanog, Klf4 and c-myc. Loss of the tumour-suppressor p53 further enhances reprogramming frequency. Like induced pluripotent stem cells, differentiated tumour cells can dedifferentiate to form CRCSCs by accumulating genetic hits, such as an increase in reprogramming factors and p53 loss (Prabhu et al., 2012). A recent paper showed the role of the NF-?B pathway in inducing dedifferentiation of villus cells and Lgr5 cells with dysregulated Wnt signalling to form tumour-initiating cells (Schwitalla et al., 2013). Thus, CRCSCs can potentially arise from differentiated CRC cells after CRCSC-specific therapy (Figure 9.2).
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