The Role of Stroma-derived Soluble TbetaRIII in Neuroblastoma

基质来源的可溶性 TbetaRIII 在神经母细胞瘤中的作用

• 批准号: 8316003
• 负责人: Erik H. Knelson
• 金额: $ 4.72万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316003
• 关键词: Address; Adrenal Glands; Adult; Benign; Biochemical; Biological Availability; Cell Differentiation process; Cell Line; Cell Proliferation; Cells; Clinical; Coculture Techniques; Data; Data Set; Development; Disease; Exhibits; Ganglioneuroblastoma; Goals; Growth; Immunocompromised Host; In Vitro; Ligands; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Neoplasm Metastasis; Neuroblastic Cell; Neuroblastoma; Neuronal Differentiation; Outcome; Pathogenesis; Pathway interactions; Peripheral Nervous System; Phosphorylation; Plasma; Proteins; Proteoglycan; Relative (related person); Reporting; Research; Role; Sampling; Schwannian Stroma; Seeds; Signal Pathway; Signal Transduction; Specimen; Staging; Stromal Cells; Stromal Neoplasm; TGF beta type III receptor; Testing; Transforming Growth Factor beta; Xenograft procedure; base; capsule; cell type; gangliocytoma; improved; in vivo; inhibitor/antagonist; migration; mutant; neoplastic cell; neuroblastoma cell; novel; outcome forecast; prevent; receptor; restoration; therapeutic target; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): The transforming growth factor beta (TGF-beta) signaling pathway regulates the development and function of the peripheral nervous system and has a significant role in the pathogenesis of the pediatric cancer, neuroblastoma (NB). TGF-beta ligands have been shown to promote neuritogenesis and neuronal differentiation of NB cells in vitro. The type III TGF-beta receptor (TbetaRIII) is a transmembrane proteoglycan which undergoes ectodomain shedding, releasing a soluble receptor form (sTbetaRIII). TbetaRIII acts as a co-receptor in the TGF-beta signaling pathway, regulating TGF-beta ligand bioavailability to mediate canonical activation of TGF-beta-stimulated transcription factors. TbetaRIII also has TGF-beta signaling-independent roles in regulating cell proliferation, migration and invasion. Decreased TbetaRIII expression has been reported in the progression of several adult cancers and has been associated with advanced-stage NB. Microarray dataset analysis demonstrates a decrease in TbetaRIII expression in malignant NB compared with benign ganglioneuroblastoma and ganglioneuroma. This analysis also reveals that TbetaRIII expression positively correlates with tumor stromal content, which is associated with improved clinical prognosis. Consistent with this result, we observe expression of TbetaRIII in the stroma of NB clinical specimens. In preliminary in vitro data, we demonstrate that restoration of TbetaRIII expression or treatment with sTbetaRIII promotes neuritogenesis and neuronal differentiation in a cell line model of NB. sTbetaRIII released from a Schwannian stromal cell line also has neuritogenic and differentiating effects on neuroblastic cells of the same lineage. While sTbetaRIII has been characterized as an inhibitor of TGF-beta signaling, functioning via ligand sequestration, the ability of sTbetaRIII to mimic the effect o TGF-beta ligands suggests a novel mechanism for sTbetaRIII function. Elucidating the molecular mechanisms directing sTbetaRIII's effects on NB tumor cell differentiation will aid in identifying therapeutic targets for this devastating pediatric cancer. Based on our preliminary data and the defined role of TGF-beta signaling in neuronal differentiation and NB pathogenesis, we hypothesize that sTbetaRIII released by the stroma promotes neuronal differentiation via canonical TGF-beta signaling to inhibit NB invasiveness.

描述（由申请人提供）：转化生长因子β（TGF-β）信号通路调节外周神经系统的发育和功能，并在儿科癌症神经母细胞瘤（NB）的发病机制中起重要作用。TGF-β配体已显示在体外促进NB细胞的轴突发生和神经元分化。III型TGF-β受体（TbetaRIII）是一种跨膜蛋白聚糖，其经历胞外域脱落，释放可溶性受体形式（sTbetaRIII）。TbetaRIII作为TGF-β信号通路中的共受体，调节TGF-β配体的生物利用度以介导TGF-β刺激的转录因子的典型活化。TbetaRIII还在调节细胞增殖、迁移和侵袭中具有TGF-β信号传导独立的作用。据报道，在几种成人癌症的进展中，TbetaRIII表达降低，并且与晚期NB相关。微阵列数据集分析表明，与良性神经节细胞瘤和神经节细胞瘤相比，恶性NB中TbetaRIII表达降低。该分析还揭示了TbetaRIII表达与肿瘤基质含量正相关，这与改善的临床预后相关。与该结果一致，我们观察到NB临床标本的基质中TbetaRIII的表达。在初步的体外数据中，我们证明了TbetaRIII表达的恢复或用sTbetaRIII治疗促进NB细胞系模型中的轴突发生和神经元分化。从施万氏基质细胞系释放的sTbetaRIII也对同一谱系的成神经细胞具有神经轴突发生和分化作用。虽然sTbetaRIII已被表征为TGF-β信号传导的抑制剂，通过配体螯合发挥作用，但sTbetaRIII模拟TGF-β配体作用的能力表明了sTbetaRIII功能的新机制。阐明指导sTbetaRIII对NB肿瘤细胞分化的作用的分子机制将有助于确定这种毁灭性儿科癌症的治疗靶点。基于我们的初步数据和TGF-β信号传导在神经元分化和NB发病机制中的确定作用，我们假设由基质释放的sTbetaRIII通过典型的TGF-β信号传导促进神经元分化以抑制NB侵袭。