LGR5 is Expressed by Ewing Sarcoma and Potentiates Wnt/β-Catenin Signaling.
LGR5 is Expressed by Ewing Sarcoma and Potentiates Wnt/β-Catenin Signaling.
复制标题
DOI：
10.3389/fonc.2013.00081
复制
发表时间：
2013
影响因子：
4.7
通讯作者：
Lawlor ER
中科院分区：
文献类型：
--
作者：
Scannell CA;Pedersen EA;Mosher JT;Krook MA;Nicholls LA;Wilky BA;Loeb DM;Lawlor ER
尤文肉瘤(ES)是一种侵袭性骨和软组织肿瘤，推测为干细胞起源，主要发生在儿童和年轻人。虽然大多数局限性ES患者可以通过强化治疗治愈，但临床病程多种多样，多达三分之一的患者在首次缓解后复发。不幸的是，人们对区分低风险和高风险疾病的生物学特征或ES疾病进展的机制知之甚少。最近的报道表明，假定的癌症干细胞存在于ES中，并可能与侵袭性表型有关。细胞表面富含亮氨酸重复序列的G蛋白偶联受体5(LGR5)是一种体细胞干细胞标记物，在几种人类癌症中发挥癌基因的作用，尤其是结直肠癌。LGR5是R-响应蛋白配体家族的受体，RSPO介导的LGR5激活增强了WNT/β-连环蛋白信号，有助于干细胞的增殖和自我更新。考虑到其假定的干细胞来源，我们调查了LGR5是否与ES的发病有关。我们发现LGR5是由ES表达的，并且它在表现出更具侵袭性的细胞和肿瘤中的表达相对增加。特别是，在可能的癌症干细胞中，LGR5的表达增加。我们还发现神经脊来源的干细胞表达LGR5，这增加了LGR5表达可能是ES细胞起源的一个特征的可能性。当暴露于WnT配体时，高表达β的ES细胞显示出LGR5-连环蛋白的核定位和TcF报告活性的强烈激活，这一点被RSPO增强。然而，调节LGR5或暴露于RSPO对增殖没有影响，证实了ES细胞中的Wnt/β-catenin信号不能概括上皮细胞中的信号。综上所述，这些研究表明Rspo-LGR5-WNT-β-Catenin轴在ES中存在并活跃，可能参与了肿瘤的发病。
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.