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
Since its initial discovery, there has been some debate about the use of CD133 as an ISC and CRCSC marker. Using lineage-tracing analysis, a study has shown that CD133/Prom1+ cells represent mouse ISCs that are capable of initiating tumours upon acquisition of β-catenin mutations (Zhu et al., 2009). However, another study shows that CD133 expression is not restricted to ISCs alone and that differentiated mouse and human normal and tumour epithelial cells also express it. Both CD133+ and CD133populations from metastatic human colon tumours are capable of tumour initiation and long-term tumour maintenance. The functional importance of CD133 in tumour growth and CRCSC biology remains unknown (Shmelkov et al., 2008).
Along with CD133, several other CRCSC markers have been identified and characterized (Figure 9.2). Lgr5, the crypt stem cell marker-positive cells have indeed been shown to initiate mouse intestinal adenomas upon acquiring APC deletion and to be responsible for adenoma growth. Lgr5+ cells in adenomas can give rise to Lgr5+ and Lgr5cells, indicating a stem cell hierarchy within CRC (Schepers et al., 2012). In similar studies, CD44, CD166 (Dalerba et al., 2007), CD26 (Pang et al., 2010), ALDH1 (Huang et al., 2009), EphB2 (Merlos-Suarez et al., 2011), Bmi1 (Kreso et al., 2014), Dclk1 (Nakanishi et al., 2013) and other CRCSC markers have been characterized (Table 9.1). Interestingly, while most commonly used CRCSC markers, such as CD44, CD133, Lgr5, Bmi1 and ALDH1, are also expressed by ISCs, Dclk1 is expressed on CRCSCs and tuft cells but not ISCs.
Figure 9.2. Overview of CRCSC biology. Colorectal tumours include a variety of cells at various stages of differentiation. CRCSCs are a rare population of stem cell-like cells within the tumour with enhanced self-renewal properties that drive long-term tumour growth, chemotherapy resistance, relapse and metastasis. Several factors govern the self-renewal and differentiation of CRCSCs, including signalling pathways and the tumour microenvironment. CRCSCs can give rise to multiple lineages within the tumour. Differentiated tumour cells can also give rise to CRCSCs via dedifferentiation. The resulting cellular plasticity contributes to tumour heterogeneity and is a major problem in cancer therapy. Various functional clones of CRCSCs can exist within a single tumour, further contributing to tumour heterogeneity. CRCSC markers, regulators and signalling pathways serve as important therapeutic targets. CRCSC-speci?c agents can be combined with chemotherapy to target both CRCSCs and bulk tumour cells.
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