Analysis of a Novel Secreted Protein in Neuroblastoma

描述（由申请人提供）： 神经母细胞瘤是儿童最常见的颅外实体瘤，占儿童癌症死亡的15%。疾病的转移性扩散是与不良结局相关的主要因素。这些肿瘤来源于胚胎神经嵴细胞。对神经嵴生长和分化信号的异常反应被认为在决定神经母细胞瘤肿瘤细胞的恶性表型中起重要作用，然而，调节这种肿瘤的增殖和转移的分子机制在很大程度上仍然未知。生长因子、细胞因子和趋化因子在神经母细胞瘤的增殖、侵袭和转移中起重要作用。我们克隆了一个新的分泌分子，命名为神经母细胞瘤衍生分泌蛋白（NDSP），从我们的微阵列为基础的分析差异基因表达在高风险的神经母细胞瘤肿瘤。我们的初步研究表明，NDSP在神经母细胞瘤细胞中高度表达，在正常人体组织中显示最小表达谱，并且其编码的蛋白质分泌到培养基中。此外，我们还发现NDSP是神经母细胞瘤细胞中神经生长因子（NGF）反应基因。这项工作的中心假设是，NDSP是一种新的神经母细胞瘤的诊断标志物，对神经母细胞瘤的生长和转移至关重要。本实验将通过分析NDSP在神经母细胞瘤中的表达模式和生物学作用来验证这一假设。 本申请的具体目的是：1）确定NDSP是否是神经母细胞瘤的潜在生物标志物; 2）确定NDSP是否参与调节神经母细胞瘤肿瘤形成和扩散。 NDSP不仅可能是治疗干预的潜在药物靶点，而且可能是潜在的诊断生物标志物。

DESCRIPTION (provided by applicant): Neuroblastoma is the most common extracranial solid tumor in children and is responsible for 15% of pediatric cancer deaths. Metastatic spread of disease is the principal factor associated with poor outcome. These tumors derive from embryonic neural crest cells. Aberrant responses to neural crest growth and differentiation signals are thought to play an important role in determining the malignant phenotype of neuroblastoma tumor cells, however, the molecular mechanisms regulating the proliferation and metastasis of this tumor remain largely unknown. Growth factors, cytokines and chemokines play important roles in tumor proliferation, invasion, and metastasis of neuroblastoma. We cloned a novel secreted molecule, named Neuroblastoma Derived Secreted Protein (NDSP), from our microarray-based analysis of differential gene expression in high risk neuroblastoma tumors. Our preliminary studies have shown that NDSP is highly expressed in neuroblastoma cells, displays a minimal expression profile in normal human tissues, and its encoded protein is secreted into culture media. In addition, we found that NDSP is a Nerve Growth Factor (NGF) responsive gene in neuroblastoma cells. The central hypothesis of this work is that NDSP is a novel diagnostic marker for neuroblastoma and essential for neuroblastoma growth and metastasis. The proposed experiments will test this hypothesis by analyzing the expression pattern and biological role of NDSP in neuroblastoma. The specific aims of this application are: 1) to determine whether NDSP is a potential biomarker for neuroblastoma; 2) to determine whether NDSP is involved in regulating neuroblastoma tumor formation and dissemination. It is likely that NDSP is not only a potential drug target for therapeutic intervention but also a potential diagnostic biomarker.