LGR5 is expressed by Ewing sarcoma and potentiates Wnt/β-catenin signaling

Christopher A. Scannell, Elisabeth A. Pedersen, Jack T. Mosher, Melanie Anne Krook, Lauren A. Nicholls, Breelyn A. Wilky, David M. Loeb, Elizabeth R. Lawlor

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numberArticle 81
JournalFrontiers in Oncology
Volume3 APR
DOIs
StatePublished - Dec 24 2013
Externally publishedYes

Fingerprint

Catenins
Ewing's Sarcoma
Neoplastic Stem Cells
Stem Cells
Ligands
Phenotype
Neoplasms
Adult Stem Cells
Neural Crest
Cell Surface Receptors
G-Protein-Coupled Receptors
Oncogenes
Leucine
Disease Progression
Young Adult
Colorectal Neoplasms
Epithelial Cells
Cell Proliferation
Recurrence
Therapeutics

Keywords

  • β-catenin
  • Ewing sarcoma
  • LGR5
  • R-spondin
  • Stem cell
  • Wnt

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Scannell, C. A., Pedersen, E. A., Mosher, J. T., Krook, M. A., Nicholls, L. A., Wilky, B. A., ... Lawlor, E. R. (2013). LGR5 is expressed by Ewing sarcoma and potentiates Wnt/β-catenin signaling. Frontiers in Oncology, 3 APR, [Article 81]. https://doi.org/10.3389/fonc.2013.00081

LGR5 is expressed by Ewing sarcoma and potentiates Wnt/β-catenin signaling. / Scannell, Christopher A.; Pedersen, Elisabeth A.; Mosher, Jack T.; Krook, Melanie Anne; Nicholls, Lauren A.; Wilky, Breelyn A.; Loeb, David M.; Lawlor, Elizabeth R.

In: Frontiers in Oncology, Vol. 3 APR, Article 81, 24.12.2013.

Research output: Contribution to journalArticle

Scannell, CA, Pedersen, EA, Mosher, JT, Krook, MA, Nicholls, LA, Wilky, BA, Loeb, DM & Lawlor, ER 2013, 'LGR5 is expressed by Ewing sarcoma and potentiates Wnt/β-catenin signaling', Frontiers in Oncology, vol. 3 APR, Article 81. https://doi.org/10.3389/fonc.2013.00081
Scannell CA, Pedersen EA, Mosher JT, Krook MA, Nicholls LA, Wilky BA et al. LGR5 is expressed by Ewing sarcoma and potentiates Wnt/β-catenin signaling. Frontiers in Oncology. 2013 Dec 24;3 APR. Article 81. https://doi.org/10.3389/fonc.2013.00081
Scannell, Christopher A. ; Pedersen, Elisabeth A. ; Mosher, Jack T. ; Krook, Melanie Anne ; Nicholls, Lauren A. ; Wilky, Breelyn A. ; Loeb, David M. ; Lawlor, Elizabeth R. / LGR5 is expressed by Ewing sarcoma and potentiates Wnt/β-catenin signaling. In: Frontiers in Oncology. 2013 ; Vol. 3 APR.
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abstract = "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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AU - Pedersen, Elisabeth A.

AU - Mosher, Jack T.

AU - Krook, Melanie Anne

AU - Nicholls, Lauren A.

AU - Wilky, Breelyn A.

AU - Loeb, David M.

AU - Lawlor, Elizabeth R.

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AB - 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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