Translational Research and Biomarkers

Annals of Surgical Oncology

, Volume 18, Issue 4, pp 1166-1174

Significance of Lgr5+ve Cancer Stem Cells in the Colon and Rectum

  • Hidekazu TakahashiAffiliated withDepartment of Gastroenterological Surgery, Osaka University Graduate School of Medicine
  • , Hideshi IshiiAffiliated withDepartment of Gastroenterological Surgery, Osaka University Graduate School of MedicineDepartment of Molecular and Cellular Biology, Division of Molecular and Surgical Oncology, Kyushu University, Medical Institute of Bioregulation
  • , Naohiro NishidaAffiliated withDepartment of Gastroenterological Surgery, Osaka University Graduate School of MedicineDepartment of Molecular and Cellular Biology, Division of Molecular and Surgical Oncology, Kyushu University, Medical Institute of Bioregulation
  • , Ichiro TakemasaAffiliated withDepartment of Gastroenterological Surgery, Osaka University Graduate School of Medicine
  • , Tsunekazu MizushimaAffiliated withDepartment of Gastroenterological Surgery, Osaka University Graduate School of Medicine
  • , Masataka IkedaAffiliated withDepartment of Gastroenterological Surgery, Osaka University Graduate School of MedicineDepartment of Molecular and Cellular Biology, Division of Molecular and Surgical Oncology, Kyushu University, Medical Institute of Bioregulation
  • , Takehiko YokoboriAffiliated withDepartment of Molecular and Cellular Biology, Division of Molecular and Surgical Oncology, Kyushu University, Medical Institute of Bioregulation
  • , Koshi MimoriAffiliated withDepartment of Molecular and Cellular Biology, Division of Molecular and Surgical Oncology, Kyushu University, Medical Institute of Bioregulation
  • , Hirofumi YamamotoAffiliated withDepartment of Gastroenterological Surgery, Osaka University Graduate School of Medicine
    • , Mitsugu SekimotoAffiliated withDepartment of Gastroenterological Surgery, Osaka University Graduate School of Medicine
    • , Yuichiro DokiAffiliated withDepartment of Gastroenterological Surgery, Osaka University Graduate School of Medicine
    • , Masaki MoriAffiliated withDepartment of Gastroenterological Surgery, Osaka University Graduate School of MedicineDepartment of Molecular and Cellular Biology, Division of Molecular and Surgical Oncology, Kyushu University, Medical Institute of Bioregulation Email author 

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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.