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

Ann Surg Oncol. 2011 Apr;18(4):1166-74. doi: 10.1245/s10434-010-1373-9. Epub 2010 Dec 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics
  • Adenoma / metabolism
  • Adenoma / pathology
  • Aged
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Female
  • Genes, myc / genetics
  • Humans
  • Immunoenzyme Techniques
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / secondary
  • Lymphatic Metastasis
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / metabolism*
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / secondary
  • RNA, Messenger / genetics
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • LGR5 protein, human
  • MIRN200 microRNA, human
  • MIRN23a microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • Receptors, G-Protein-Coupled