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

Bmi1 constitutes a component of the Polycomb transcriptional repressor complex that functions as a regulator of self-renewal and plays an essential role in maintaining chromatin silencing of neural and haematopoietic progenitor cells (De Mey and Freund, 2013). Bmi1+ cells have been visualized in the small intestine of mice, where they most frequently occupy the +4 position, using a LacZ reporter gene. Bmi1+ cells cycle at a lower frequency than CBC cells or Lgr5+ cells and are represented at a much lower frequency in the duodenum and jejunum. By contrast to Lgr5+ cells, Bmi1-expressing cells are not observed in distal parts of the small intestine or colon. It is somewhat unclear if this is related to silencing of the transgene or indicative of segment-specific expression of Bmi1 in ISCs (Sangiorgi and Capecchi, 2008). Indeed, targeted diphtheria toxin-dependent killing of Bmi1+ cells caused crypt death in the small intestine. A follow-up study showed that Bmi1+ cells represent a distinct radiation-resistant population of ISCs from that of Lgr5+ cells in the small intestine (Yan et al., 2012). Furthermore, it has been suggested that Bmi1+ cells function as a stem cell reserve, since following selective diphtheria toxin ablation of Lgr5+ CBCs, Bmi1+ cells become proliferative and rescue crypt homeostasis by providing progeny that replenish Lgr5+ CBCs (Tian et al., 2011). This indicates that, upon injury, Bmi1+ cells may function as stem cells, replenishing CBCs and maintaining tissue homeostasis. Thus, it has been proposed that Lgr5+ cells represent adult stem cells that maintain tissue homeostasis, whereas Bmi1+ cells serve to maintain epithelial compensatory proliferation and regeneration following injury. From this, it can be concluded that the small intestine should harbour two distinct ISC populations that address two operationally distinct conditions.

However, the specificity of enforced Bmi1+ expression to the +4 position has been brought into question, and Bmi1 mRNA can be detected in Lgr5+ cells (Barker et al., 2012). It has been suggested that Bmi1 expression is not specific to the +4 position but can be detected throughout the proliferative epithelium and crypt base. Furthermore, Bmi1-based lineage tracking can be initiated throughout the small-intestinal epithelium, including Lgr5+ CBCs. Thus, it is not currently clear whether Bmi1 selectively marks ISCs or how Bmi1 expression might relate to other ISC markers. On the other hand, chemical targeting of Bmi1 has been suggested to target cancer-initiating cells and serve as a new therapeutic approach for the treatment of CRC (Kreso et al., 2014).

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