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


METHODS
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.
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Hidekazu
H
Takahashi
Hideshi
H
Ishii
Naohiro
N
Nishida
Ichiro
I
Takemasa
Tsunekazu
T
Mizushima
Masataka
M
Ikeda
Takehiko
T
Yokobori
Koshi
K
Mimori
Hirofumi
H
Yamamoto
Mitsugu
M
Sekimoto
Yuichiro
Y
Doki
Masaki
M
Mori
D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D012333:RNA, Messenger / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C116884:LGR5 protein, human; C533896:MIRN200 microRNA, human; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled