caa a22 4500 445336188 CHVBK 20180317142756.0 cr unu---uuuuu 170323e20110401xx s 000 0 eng 10.1245/s10434-010-1373-9 doi (NATIONALLICENCE)springer-10.1245/s10434-010-1373-9 Significance of Lgr5+ve Cancer Stem Cells in the Colon and Rectum [Elektronische Daten] [Hidekazu Takahashi, Hideshi Ishii, Naohiro Nishida, Ichiro Takemasa, Tsunekazu Mizushima, Masataka Ikeda, Takehiko Yokobori, Koshi Mimori, Hirofumi Yamamoto, Mitsugu Sekimoto, Yuichiro Doki, Masaki Mori] 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. Society of Surgical Oncology, 2010 Takahashi Hidekazu Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut Ishii Hideshi Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut Nishida Naohiro Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut Takemasa Ichiro Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut Mizushima Tsunekazu Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut Ikeda Masataka Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut Yokobori Takehiko Department of Molecular and Cellular Biology, Division of Molecular and Surgical Oncology, Kyushu University, Medical Institute of Bioregulation, Ohita, Japan aut Mimori Koshi Department of Molecular and Cellular Biology, Division of Molecular and Surgical Oncology, Kyushu University, Medical Institute of Bioregulation, Ohita, Japan aut Yamamoto Hirofumi Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut Sekimoto Mitsugu Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut Doki Yuichiro Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut Mori Masaki Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut Annals of Surgical Oncology Springer-Verlag 18/4(2011-04-01), 1166-1174 1068-9265 18:4<1166 2011 18 10434 https://doi.org/10.1245/s10434-010-1373-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1245/s10434-010-1373-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Takahashi Hidekazu Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut NATIONALLICENCE 700 1- Ishii Hideshi Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut NATIONALLICENCE 700 1- Nishida Naohiro Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut NATIONALLICENCE 700 1- Takemasa Ichiro Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut NATIONALLICENCE 700 1- Mizushima Tsunekazu Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut NATIONALLICENCE 700 1- Ikeda Masataka Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut NATIONALLICENCE 700 1- Yokobori Takehiko Department of Molecular and Cellular Biology, Division of Molecular and Surgical Oncology, Kyushu University, Medical Institute of Bioregulation, Ohita, Japan aut NATIONALLICENCE 700 1- Mimori Koshi Department of Molecular and Cellular Biology, Division of Molecular and Surgical Oncology, Kyushu University, Medical Institute of Bioregulation, Ohita, Japan aut NATIONALLICENCE 700 1- Yamamoto Hirofumi Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut NATIONALLICENCE 700 1- Sekimoto Mitsugu Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut NATIONALLICENCE 700 1- Doki Yuichiro Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut NATIONALLICENCE 700 1- Mori Masaki Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan aut NATIONALLICENCE 773 0- Annals of Surgical Oncology Springer-Verlag 18/4(2011-04-01), 1166-1174 1068-9265 18:4<1166 2011 18 10434 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer