Significance of Lgr5^+ve cancer stem cells in the colon and rectum

Purpose: Although recent studies show that leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5)^+ve cells targeted by Wnt drive self-renewal in the skin and gastrointestinal organs, the clinicopathological significance of Lgr5^+ve cancer stem cells (CSCs) of the colon remains to be elucidated. Experimental Design. We studied the Wnt-targeted Lgr5 pathway in colorectal cancer (CRC). The expression of LGR5, c-MYC, p21CIP1/WAF1/CDKN1A, glutaminase (GLS), and miRs-23a and -23b (that target LGR5 and GLS) was evaluated by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR). The Lgr5 protein was evaluated by immunohistochemistry. The clinical relevance of gene expression in terms of patient survival was also evaluated. Results: Overexpression of LGR5 was significantly associated with expression of c-MYC, p21CIP1/WAF1/ CDKN1A, and GLS (p<0.0001), and inversely associated with miR-23a/b (p<0.05). Immunohistochemical analysis indicated that Lgr5 may be embedded in benign adenomas, localized at the tumor-host interface, and detectable over a broad area in established tumors. High level of LGR5 expression was associated with poor prognosis for CRC cancer patients (disease-free survival; p<0.05). Conclusions: This study supports a significant role for LGR5 in the CSC hypothesis in CRC: (1) Lgr5^+ve CSCs, presumably derived from normal stem cells in colonic crypts, proliferate, and the gene is overexpressed during CRC development; (2) LGR5 expression is associated with activation of Wnt pathway, including oncogenic c-MYC and high energy production via glutaminolysis; (3) LGR5 expression may be a poor prognostic factor for CRC patients. Further study of LGR5 should contribute to the development of CSC-based cancer therapeutics.