CRCSC-mediated chemotherapy resistance and CRC recurrence

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 clinical relevance of CRCSCs and their markers has been explored in several studies. CRCSCs are of particular interest in the clinic, due to their chemotherapy resistance (Figure 9.2). For example, CRCSC populations of CD133+ and CD26+ cells are resistant to the commonly used CRC chemotherapy agents 5-fluorouracil and oxaliplatin, while CD26 and CD133cells are sensitive to chemotherapy (Todaro et al., 2007; Pang et al., 2010). ISCand CRCSC-specific gene signatures have been used to identify CRCSCs in patient tumours. Both signatures have been shown to predict poor prognosis and disease relapse (de Sousa et al., 2011b; Merlos-Suarez et al., 2011). Polymorphisms in CRCSC marker genes such as ALDH1, CD44 and Lgr5 have been shown to predict recurrence in CRC patients treated with 5-fluorouracil-based therapy (Gerger et al., 2011).

Table 9.1. Biomarkers of gastrointestinal stem cells.

Biomarker Expression pattern/location Proliferation status Tissue regeneration Intestinal hyperplasia
Bmi1 Frequent expression at +4 positions in proximal small intestine; minimal expression in CBC; no lineage tracing in colon Marks relatively quiescent cells Yes, 20-fold increased proliferation of Bmi1+ cells following radiation Yes, deletion of APC in Bmi1+ cells causes small-intestinal adenomas
H2B-YFP label-retaining cells (LRCs) Crypt base, slight predomination at the +3 position in the small intestine; approximately two per whole crypt; not detected in the colon. Gene expression overlaps with Lgr5+ cells; combined secretory and stem cell expression signature Quiescent. LRCs function as progenitor cells to Paneth and enteroendocrine cells during normal homeostasis Yes, increased proliferation following injury; LRCs function as stem cells under conditions of injury (hydroxyurea, doxorubicin, radiation)  N/A
Hopx Populates the entire small intestine; frequent around +4 position Relatively quiescent. Lgr5+ cells can give rise to Hopx+ cells in vitro Actively proliferating following radiation-induced injury N/A
Lgr5 Expressed in CBC cells of the small intestine and columnar ‘vacuolated’ cells of the descending colon Proliferative Indispensible for regeneration following radiation-induced injury Yes, deletion of APC in Lgr5+ cells results in persistent intestinal adenomas
Lrig1 Broadly expressed in small intestine and colon; highest levels found in Lgr5+ cells Proliferative Proliferative following injury; radiation resistant Negatively regulates ErbB signalling and limits expansion of the stem cell niche. Loss of APC in Lrig1 leads to adenoma formation
TERT Infrequently expressed, primarily at the +4 position in the small intestine Quiescent Actively proliferating following radiation-induced injury N/A


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