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

The Wnt target gene, G protein-coupled receptor Lgr5, which acts as a receptor for a small family of Wnt pathways called R-spondins, has been shown to be a specific marker for ISCs in the mouse small intestine and colon (Barker et al., 2012). The expression of Lgr5 is controlled by Wnt signals and Lgr5 is an optional component of the Wnt receptor complex. The generation of mice expressing EGFP under the Lgr5 promoter has helped identify living ISCs in their guts, as has a tool for in vivo lineage tracing (Barker et al., 2007). Cells expressing EGFP under the Lgr5 promoter represent a long-lived multipotent stem cell lineage. Lgr5+ cells have been shown to be capable of self-renewal and differentiation into multiple epithelial lineages in vitro and in vivo. A single Lgr5+ cell was capable of generating crypt-like organoid structures in vitro, containing cells with epithelial morphology that expressed markers consistent with multilineage differentiation. Each intestinal crypt contains around 15 Lgr5+ cells, with a slender wedge-like morphology, which are in contact with Paneth cells located at the crypt bottom and divide once every day. Paneth cells provide an extracellular milieu that maintains the stem cell niche, at least in vitro, where it has been demonstrated that Paneth cells provide EGF, Wnt and Notch signals to Lgr5+ cells (Sato et al., 2011). In addition, Lgr5+ cells residing at the bases of colonic crypts have also been identified as adult stem cells. In the crypts of the ascending colon, CD24+ or deep secretory cells (DSCs) residing between Lgr5+ cells may represent the Paneth cell equivalents (De Mey and Freund, 2013). CRC is more frequent in the descending colon of humans and is thus of particular interest. In mice, this segment lacks DSCs but contains mature Muc2-secreting cells, referred to as goblet-like cells (GLCs), that express CD24 (De Mey and Freund, 2013). In this colonic segment, high Lgr5 expression is found in columnar ‘vacuoled cells’, which can be detected next to GLCs, and it has been shown that Lgr5+ cells indeed function as stem cells in the descending colon of mice. There is evidence that Lgr5+ cells in early intestinal adenoma function as tumour stem cells, since deletion of Apc can lead within days to their transformation and fuels the growth of microadenomas (Barker et al., 2009). These transformed Lgr5+ cells represent 5 – 10% of the cell population in the formed adenomas and retain their hierarchical position even when CRE-recombinase causes concomitant APC deletion and expression of mutant KRAS in Lgr5+ cells (Schepers et al., 2012). Monoclonal antibodies towards Lgr5 have been used to identify a population that behaves like CRCSCs in vitro from primary colorectal tumour cells (Kemper et al., 2012). The relevance for the presence of different levels of Lgr5-expressing cells in CRC with respect to clinical parameters remains to be addressed, but data suggest that Lgr5 may be a selective marker for CRCSCs. Recent data employing single-stem-cell in vivo live imaging indicate that the short-term dynamics of Lgr5+ cells in the upper part of the stem cell niche (border cells) are occasionally passively displaced into the transit-amplifying zone after the division of proximate cells, which suggests that maintenance of stem cell properties may be uncoupled from division (Ritsma et al., 2014). Lgr5+ cells at the crypt base (central cells) experience a survival advantage compared to border cells and are three times more likely to fully colonize a crypt at steady state. However, all Lgr5+ cells can move in the stem cell niche and are subsequently able to function as a long-term equipotent stem cell pool (Figure 9.1).

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