Abstract
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.
Highlights
Ewing sarcoma (ES) is a malignant tumor of the bone and soft tissue that can present at any age but predominantly occurs in adolescents and young adults
The specificity of commercially available antibodies for studies of human leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) remains inadequate for immuno-histochemical studies so we limited our evaluation of LGR5 expression to quantitative RT-PCR analysis
We found that levels of LGR5 were highest in putative ES cancer stem cells as well as primary tumor biopsies obtained from patients with rapidly progressive and drug-resistant disease
Summary
Ewing sarcoma (ES) is a malignant tumor of the bone and soft tissue that can present at any age but predominantly occurs in adolescents and young adults. These tumors are genetically defined by recurrent chromosomal translocations that result in the creation of novel fusion oncogenes, most commonly EWSFLI1 (Balamuth and Womer, 2010). These tumors often have an aggressive course with one quarter of patients presenting with gross metastatic disease at the time of diagnosis. The stem cell phenotype and aggressive nature of ES raise the question of whether stem cell markers could be useful in understanding the origin and pathogenesis of this enigmatic disease
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