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

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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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Acknowledgment

This work was supported in part by a grant-in-aid for scientific research on Priority Areas (20012039), a grant-in-aid for scientific research (S, 21229015; C, 20590313), and a grant-in-aid for Young Scientists (B, 21791287) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

    Hidekazu Takahashi MD, Hideshi Ishii MD, PhD, Naohiro Nishida MD, Ichiro Takemasa MD, PhD, Tsunekazu Mizushima MD, PhD, Masataka Ikeda MD, PhD, Hirofumi Yamamoto MD, PhD, Mitsugu Sekimoto MD, PhD, Yuichiro Doki MD, PhD, FACS & Masaki Mori MD, PhD, FACS

  2. Department of Molecular and Cellular Biology, Division of Molecular and Surgical Oncology, Kyushu University, Medical Institute of Bioregulation, Ohita, Japan

    Hideshi Ishii MD, PhD, Naohiro Nishida MD, Masataka Ikeda MD, PhD, Takehiko Yokobori MD, PhD, Koshi Mimori MD, PhD & Masaki Mori MD, PhD, FACS

Authors
  1. Hidekazu Takahashi MD
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  2. Hideshi Ishii MD, PhD
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  3. Naohiro Nishida MD
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  4. Ichiro Takemasa MD, PhD
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  5. Tsunekazu Mizushima MD, PhD
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  6. Masataka Ikeda MD, PhD
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  7. Takehiko Yokobori MD, PhD
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  8. Koshi Mimori MD, PhD
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  9. Hirofumi Yamamoto MD, PhD
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  10. Mitsugu Sekimoto MD, PhD
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Corresponding author

Correspondence to Masaki Mori MD, PhD, FACS.

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Takahashi, H., Ishii, H., Nishida, N. et al. Significance of Lgr5+ve Cancer Stem Cells in the Colon and Rectum. Ann Surg Oncol 18, 1166–1174 (2011). https://doi.org/10.1245/s10434-010-1373-9

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  • DOI: https://doi.org/10.1245/s10434-010-1373-9

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