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  • Title: Significance of Lgr5(+ve) cancer stem cells in the colon and rectum.
    Author: Takahashi H, Ishii H, Nishida N, Takemasa I, Mizushima T, Ikeda M, Yokobori T, Mimori K, Yamamoto H, Sekimoto M, Doki Y, Mori M.
    Journal: Ann Surg Oncol; 2011 Apr; 18(4):1166-74. PubMed ID: 21125339.
    Abstract:
    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.
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