Expression of Lgr5, a marker of intestinal stem cells, in colorectal cancer and its clinicopathological significance

He, Songbing; Zhou, Hao; Zhu, Xinguo; Hu, Shuiqing; Fei, Min; Wan, Daiwei; Gu, Wen; Yang, Xiaodong; Shi, Daren; Zhou, Jian; Zhou, Jin; Zhu, Zheng; Wang, Liang; Li, Dechun; Zhang, Yanyun

doi:10.1016/j.biopha.2014.03.016

Cited by 57 publications

(53 citation statements)

References 32 publications

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“…Likewise, we found that LGR5 positivity was higher in GCs with nuclear b-catenin expression. This close correlation between LGR5 and increased Wnt signaling was also reported in colon cancers [15,34] as well as hepatocellular carcinomas [29], in which overexpression of LGR5 was observed in 87.5 % of hepatocellular carcinomas with mutation of b-catenin exon 3. These findings are in accordance with the fact that LGR5 is one of the Wnt target genes and functions to augment canonical Wnt signals.…”

Section: Discussionsupporting

confidence: 77%

“…Subsequent studies investigated the clinical and functional implications of LGR5 in a variety of human malignant tumors-for example, colorectal cancers [14][15][16], GCs [17,18], and hepatocellular carcinomas [19]. Even in lung adenocarcinomas [20] and gliomas [21], LGR5 expression and its clinicopathological significance were examined although LGR5-expressing stem cells normally do not exist in the lung and brain.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic significance of leucine-rich-repeat-containing G-protein-coupled receptor 5, an intestinal stem cell marker, in gastric carcinomas

2015

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Background Cells expressing LGR5, an intestinal stem cell marker, have been suggested as cancer stem cells in human colon cancers. Previously, we discovered that LGR5-expressing cells exist in the gastric antrum and remarkably increase in number in intestinal metaplasia. In addition, most gastric adenomas contain abundant LGR5-expressing cells coexpressing intestinal stem cell signatures. However, LGR5 expression in gastric cancers (GCs) and its prognostic significance remain unknown. Methods We examined the LGR5 expression in GC tissues by real time-PCR and RNA in situ hybridization, and analyzed its clinicopathological relevance and prognostic value. The effects of LGR5 on cancer cell proliferation and migration were assessed with an in vitro transfection technique. Results LGR5 expression was significantly lower in GCs than in matched nontumorous gastric mucosa. RNA in situ hybridization on tissue microarrays showed that 7 % of GCs were positive for LGR5. LGR5 positivity was associated with old age, well to moderate differentiation, and nuclear b-catenin positivity. Although LGR5 did not show any prognostic significance for all GC cases, it was associated with poor survival in GCs with nuclear b-catenin expression. LGR5 expression was induced by transfection in GC cell lines with abnormal Wnt activation, which, however, showed no influence on the growth and migration of GC cells. Conclusion A small portion of GCs expressed LGR5. Although LGR5 was associated with poor survival in GCs with nuclear b-catenin, LGR5 expression in GC cells had no effects on the growth and migration, requiring a further study exploring a biological role of LGR5 in GCs.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Prognostic significance of leucine-rich-repeat-containing G-protein-coupled receptor 5, an intestinal stem cell marker, in gastric carcinomas

2015

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“…LGR5 was shown to increase drug resistance, and in colon primary tumors, LGR5-high expression correlated with chemoresistance and lower disease-free and overall survival (16,17,20,23,42,43). Thus, an LGR5-targeting ADC may not only effectively treat gastrointestinal tumors, but also function to eliminate CSCs.…”

Section: Discussionmentioning

confidence: 99%

LGR5-Targeted Antibody–Drug Conjugate Eradicates Gastrointestinal Tumors and Prevents Recurrence

Gong

Azhdarinia

Ghosh

et al. 2016

Molecular Cancer Therapeutics

119

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Gastrointestinal cancer is one of the leading causes of cancerrelated mortality in men and women worldwide. The adult stem cell marker LGR5 (leucine-rich repeat-containing, G proteincoupled receptor 5) is highly expressed in a significant fraction of gastrointestinal tumors of the colon, liver, pancreas, and stomach, relative to normal tissues. LGR5 is located on the cell surface and undergoes rapid, constitutive internalization independent of ligand. Furthermore, LGR5-high cancer cells have been shown to exhibit the properties of tumor-initiating cells or cancer stem cells (CSC). On the basis of these attributes, we generated two LGR5-targeting antibody-drug conjugates (ADC) by tethering the tubulin-inhibiting cytotoxic drug monomethyl auristatin E to a highly specific anti-LGR5 mAb via a protease cleavable or noncleavable chemical linker and compared them in receptor binding, cell internalization, and cytotoxic efficacy in cancer cells. Here, we show that both ADCs bind LGR5 with high specificity and equivalent nanomolar affinity and rapidly internalize to the lysosomes of LGR5-expressing gastrointestinal cancer cells. The anti-LGR5 ADCs effectively induced cytotoxicity in LGR5-high gastrointestinal cancer cells, but not in LGR5-negative or -knockdown cancer cell lines. Overall, we demonstrate that the cleavable ADC exhibited higher potency in vitro and was able to eradicate tumors and prevent recurrence in a xenograft model of colon cancer. These findings provide preclinical evidence for the potential of LGR5-targeting ADCs as effective new therapeutics for the treatment and eradication of gastrointestinal tumors and CSCs with high LGR5 expression. Mol Cancer Ther; 15(7); 1580-90. Ó2016 AACR.

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“…He et al (18) demonstrated various levels of LGR5 expression in five colorectal cancer cell lines by quantitative RT-PCR. The study reported high LGR5 expression levels in SW620, Caco-2 and SW480 cells, and low levels in LoVo and HCT116 (18). Another study carried out by Ku et al (19) focused on the establishment of 13 human colorectal carcinoma cell lines.…”

Section: Discussionmentioning

confidence: 99%

Comparison of leucine-rich repeat-containing G protein-coupled receptor 5 expression in different cancer and normal cell lines

et al. 2016

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Abstract. Evaluating the expression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) may be useful for predicting the best models and achieving more accurate results in cancer research. Therefore, the aim of the present study was to analyze the LGR5 expression levels in different cell lines. Eight commonly used cell lines were assessed (COS-7, NIH3T3, HEK293, VERO, HeLa, BHK, HepG2 and AGS). All the cell lines were cultured in RPMI-1640 medium contain 10% fetal calf serum at 37˚C in humidified conditions with 5% CO 2 . According to the western blotting results, LGR5 was expressed in all cell lines. Densitometry results of LGR5 expression in the different cell lines showed that high LGR5 expression levels were apparent in BHK, AGS, VERO and NIH3T3 cell lines compared with the other cell lines. The results indicate that for the normal and cancer cell lines, BNK and AGS may be a better choice, respectively, for in vitro cancer studies. IntroductionCancer has become the major cause of mortality in certain countries in the 21st century (1). There are three models for cancer heterogeneity. Tumor heterogeneity is attained through genetic or epigenetic modifications. The stochastic model, as the first model, indicates that all tumor cells potentially are capable of self-renewal or differentiation, and are tumorigenic (2). In the second model, the hierarchical model, which is also known as the cancer stem cell (CSC) model of tumor growth, the ability of self-renew is considered for only a subset of tumor cells; the CSCs. These cells generate committed progenitor cells with limited proliferative potential, which ultimately lead to terminal differentiation (3-5). The third model is known as the complex model and this model suggests that epigenetic changes can potentially influence the tumor cell phenotype and function due to micro-environmental factors, thereby influencing tumor heterogeneity (2).Recently, a new CSC theory, known as tumor stem cells or tumor-initiating cells, has emerged. A CSC was precisely defined by the American Association for Cancer Research in 2006 as a cell within a tumor that has positive susceptibility to self-renew and to reason the heterogeneous progeny of cancer cells that are contained within the tumor (6). The CSC model was previously described for hematological malignancies in 1997 (7).Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is considered an intestinal stem cell marker (8).LGR5 has a transducer role in the Wnt signaling pathway (9,10). This signaling pathway is well known to be involved in the embryogenesis and carcinogenesis process (11). Also recognized as GPR49, LGR5 is a member of the G protein-coupled receptors, the largest family of cell-surface molecules involved in a signaling pathway. The size of the LGR5 gene is ~144 kb and it is located at position 12q22-q23 of chromosome 12. The LGR5 protein has seven transmembrane domains. Experimental findings showed that this protein in the mature form contains <17 leucine-rich repeats, each comp...

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Expression of Lgr5, a marker of intestinal stem cells, in colorectal cancer and its clinicopathological significance

Cited by 57 publications

References 32 publications

Prognostic significance of leucine-rich-repeat-containing G-protein-coupled receptor 5, an intestinal stem cell marker, in gastric carcinomas

Prognostic significance of leucine-rich-repeat-containing G-protein-coupled receptor 5, an intestinal stem cell marker, in gastric carcinomas

LGR5-Targeted Antibody–Drug Conjugate Eradicates Gastrointestinal Tumors and Prevents Recurrence

Comparison of leucine-rich repeat-containing G protein-coupled receptor 5 expression in different cancer and normal cell lines

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