A novel splice variant of the stem cell marker LGR5/GPR49 is correlated with the risk of tumor-related death in soft-tissue sarcoma patients

Rot, Swetlana; Täubert, Helge; Bache, Matthias; Greither, Thomas; Würl, Peter; Eckert, Alexander W.; Schubert, Johannes; Vordermark, Dirk; Kappler, Matthias

doi:10.1186/1471-2407-11-429

Cited by 24 publications

(23 citation statements)

References 22 publications

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“…Data to support a potential role for LGR5 in tumors of mesenchymal origin is also now beginning to emerge. A recent report by Rot et al (2011) described a novel splice variant of LGR5 in the context of soft tissue sarcoma and reported that low level expression of this variant transcript (which lacks exon 5) was associated with worse overall and event free survival. In addition, the LGR5 locus was recently identified to be among the most frequently amplified loci in a genome-wide study of soft tissue sarcomas (copy number in top 1% of nearly 19,000 genes) suggesting that up-regulation of LGR5 may contribute to sarcoma pathogenesis (Barretina et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

LGR5 is Expressed by Ewing Sarcoma and Potentiates Wnt/β-Catenin Signaling

Scannell¹,

Pedersen²,

Mosher³

et al. 2013

Front. Oncol.

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Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor of putative stem cell origin that predominantly occurs in children and young adults. Although most patients with localized ES can be cured with intensive therapy, the clinical course is variable and up to one third of patients relapse following initial remission. Unfortunately, little is yet known about the biologic features that distinguish low-risk from high-risk disease or the mechanisms of ES disease progression. Recent reports have suggested that putative cancer stem cells exist in ES and may contribute to an aggressive phenotype. The cell surface receptor leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a somatic stem cell marker that functions as an oncogene in several human cancers, most notably colorectal carcinoma. LGR5 is a receptor for the R-spondin (RSPO) family of ligands and RSPO-mediated activation of LGR5 potentiates Wnt/β-catenin signaling, contributing to stem cell proliferation and self-renewal. Given its presumed stem cell origin, we investigated whether LGR5 contributes to ES pathogenesis. We found that LGR5 is expressed by ES and that its expression is relatively increased in cells and tumors that display a more aggressive phenotype. In particular, LGR5 expression was increased in putative cancer stem cells. We also found that neural crest-derived stem cells express LGR5, raising the possibility that expression of LGR5 may be a feature of ES cells of origin. LGR5-high ES cells showed nuclear localization of β-catenin and robust activation of TCF reporter activity when exposed to Wnt ligand and this was potentiated by RSPO. However, modulation of LGR5 or exposure to RSPO had no impact on proliferation confirming that Wnt/β-catenin signaling in ES cells does not recapitulate signaling in epithelial cells. Together these studies show that the RSPO-LGR5-Wnt-β-catenin axis is present and active in ES and may contribute to tumor pathogenesis.

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Section: Discussionmentioning

confidence: 99%

LGR5 is Expressed by Ewing Sarcoma and Potentiates Wnt/β-Catenin Signaling

Scannell¹,

Pedersen²,

Mosher³

et al. 2013

Front. Oncol.

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“…Recently, it was characterized as a marker for stem cells in soft tissue sarcoma (38). In this study, we attempted to use antibodies to LGR5 as a marker for stem cells in human colon cancer.…”

Section: Resultsmentioning

confidence: 99%

Use of multiple biomarkers for the localization and characterization of colon cancer stem cells by indirect immunocytochemistry

et al. 2012

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Abstract. In this study, we used LGR5, γ-synuclein, p53, KRAS and epiregulin antibodies to localize stem cells by indirect immunocytochemistry in paraffin sections of normal and cancerous colon tissues. In the normal colon tissue, no staining of cells with LGR5, γ-synuclein, p53 and KRAS antibodies was observed, apart from a few scattered cells in between the colon villi that were faintly stained with antibodies to LGR5. Staining of highly differentiated cancer tissue with LGR5 antibodies revealed single cells or clusters of up to 4 cells in the interior space of the carcinoma cell layers. Staining of poorly differentiated cancer tissues (stage I-IV) revealed 9-81 clustered stem cells. The number of clustered stem cells increased significantly with the tumor stage, when comparing stage II to stage IV (p<00048). Occasionally, the clustered stem cells appeared in the interphase between the colon stroma and the tumor tissue. Surprisingly, antibodies to p53 clearly stained the clusters of stem cells both in the nuclei and the cytoplasm. The staining of the nuclei of other cells in the undifferentiated tumors was in general weaker, and no staining was found in the cytoplasm. Antibodies to γ-synuclein heavily stained the endothelial cells of the blood vessels and some other scattered cells in the highly differentiated tumors. Antibodies to γ-synuclein heavily stained the stem cells in both the cytoplasm and the nuclei of poorly differentiated tumors. Antibodies to KRAS stained the cytoplasm and the nuclei of stem cells in poorly differentiated tumors and also stained the cytoplasm of some scattered cells. Antibodies to epiregulin stained the cytoplasm of normal colon tissue cells in the crypt-villus axis. The antibodies weakly stained the highly differentiated tumor cells and moderately stained the moderately differentiated tumor cells.Of note, the antibodies intensively stained the clustered stem cells of the poorly differentiated tumor cells. These antibodies also clearly stained the clustered stem cells of poorly differentiated tumors but were not specific as they clearly stained cells in the crypt-villus axis of the normal colon wall. Our results show that LGR5 antibodies can serve as a reliable marker for colon cancer stem cells. Once the colon stem cells are identified, the targeting of specific drugs to kill these cells should be attempted in the future in order to cure this disease. Moreover, the fact that we did not find any stained cells with antibodies to LGR5 in normal tissues apart from a few scattered cells, suggests that the normal colon stem cells differ from the tumor stem cells at least as regards the expression of this protein.In addition, antibodies to γ-synuclein, p53 and KRAS only stained the tumor stem cells and not the normal tissue. Thus, they can serve as multiple biomarkers for the localization of colon cancer stem cells by indirect immunofluorescence.

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“…In recent years, many studies have revealed that LGR5 is overexpressed in various types of tumors, including colorectal cancer[ 15 ], ovarian tumor[ 16 ], hepatocellular carcinoma[ 17 ], basal cell carcinoma[ 18 ], and esophageal adenocarcinoma[ 19 ]. High LGR5 expression is associated with the initiation, invasion, and metastasis of tumors[ 20 , 21 ], suggesting the potential role of LGR5 in tumorigenesis. Additionally, LGR5 has been recognized as a cancer stem cell marker for colorectal cancers[ 22 ].…”

Section: Introductionmentioning

confidence: 99%

LGR5 promotes the proliferation and tumor formation of cervical cancer cells through the Wnt/β-catenin signaling pathway

2014

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Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a seven transmembrane receptor known as a potential stem cell marker for intestinal crypts and hair follicles, has recently been found to be overexpressed in some types of human cancers. However, the role of LGR5 in cervical cancer remains unclear. In this study, the expression of LGR5 gradually increases from normal cervix to cervical cancer in situ and to cervical cancers as revealed by immunohistochemistry and western blot analyses. Through knocking down or overexpressing LGR5 in SiHa and HeLa cells, the expression level of LGR5 was found to be positively related to cell proliferation in vitro and to tumor formation in vivo. Further investigation indicated that LGR5 protein could significantly promote the acceleration of cell cycle. Moreover, the TOP-Flash reporter assay and western blot for β-catenin, cyclinD1, and c-myc proteins, target genes of the Wnt/β-catenin pathway, indicated that LGR5 significantly activated Wnt/β-catenin signaling. Additionally, the blockage of Wnt/β-catenin pathway resulted in a significant inhibition of cell proliferation induced by LGR5. Taken together, these results demonstrate that LGR5 can promote proliferation and tumor formation in cervical cancer cells by activating the Wnt/β-catenin pathway.

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A novel splice variant of the stem cell marker LGR5/GPR49 is correlated with the risk of tumor-related death in soft-tissue sarcoma patients

Cited by 24 publications

References 22 publications

LGR5 is Expressed by Ewing Sarcoma and Potentiates Wnt/β-Catenin Signaling

LGR5 is Expressed by Ewing Sarcoma and Potentiates Wnt/β-Catenin Signaling

Use of multiple biomarkers for the localization and characterization of colon cancer stem cells by indirect immunocytochemistry

LGR5 promotes the proliferation and tumor formation of cervical cancer cells through the Wnt/β-catenin signaling pathway

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