PHENOTYPIC PLASTICITY IN NEUROBLASTOMA

神经母细胞瘤的表型可塑性

• 批准号: 6329036
• 负责人: ROBERT A ROSS
• 金额: $ 20.96万
• 依托单位: FORDHAM UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-10 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6329036
• 关键词: cell differentiation; cell line; cell type; gene expression; genetic regulation; genetic regulatory element; human tissue; messenger RNA; natural gene amplification; neoplastic transformation; neuroblastoma; neurogenesis; neurogenetics; phenotype; protooncogene; stem cells; tissue /cell culture

DESCRIPTION: (adapted from the investigator's abstract) Neuroblastoma, a tumor of the embryonic neural crest, is highly malignant and poorly responsive to conventional therapy, yet tumor cells retain the capacity for neuronal differentiation. This cancer is ultimately fatal in most patients and thus there is an urgent need to identify new agents and treatment strategies. The long-term goal is to understand the relationship between malignancy and cell differentiation state. Cell phenotype and amplification of the N-myc proto-oncogene are two factors that modulate the malignant potential of neuroblastoma. In cell lines, N-myc expression and malignancy are dramatically affected by cell differentiation state. Neuroblastic cells express high levels of N-myc and are highly tumorigenic whereas non-neuronal S-type cells from the same parental cell line contain markedly lower amounts of N-myc RNA/protein and are non-tumorigenic. The two cell types can arise from a third cell type, a more malignant I-type stem cell. Moreover, experimentally induced changes in cell phenotype can directly affect N- myc expression and transformation state. These observations form the basis for our central hypothesis: Cell differentiation state determined by lineage-specific as well as environmental factors, directly regulates N-myc expression and, thereby, the malignant potential of neuroblastoma cells. One lineage-specific factor regulating N-myc expression is HuD, a neuronal-specific RNA-binding protein. HuD appears in early neurogenesis and is expressed in all neurons. HuD binds to N-myc mRNA and, in antisense-HuD transfectants, its down-regulation results in reduced N-myc expression. The two aims of this proposal examine different aspects of this hypothesis. The focus of Aim #1 is to determine the mechanism(s) by which HuD interacts with N-myc mRNA and thereby regulates its expression and, as a corollary, whether loss of one HuD allele is a critical factor in the development of N-myc amplification and tumor aggressiveness. Studies proposed in Aim # 2 will establish whether the well characterized cell types found in human neuroblastoma cell lines (particularly I-type stem cells) are present in tumors and, if so, whether their presence correlates with tumor stage, aggressiveness, or site of origin. Knowledge gained of the differentiation status of cells in tumors with a favorable or unfavorable prognosis and of factors that can directly affect cellular differentiation, and thereby malignant potential, is highly likely to have important application to the treatment of neuroblastoma.

描述：（改编自研究者的摘要） 神经母细胞瘤是一种胚胎神经嵴肿瘤，发病率很高 恶性且对常规治疗反应不佳，但肿瘤细胞 保留神经元分化的能力。这种癌症是 大多数患者最终会死亡，因此迫切需要 确定新的药物和治疗策略。长期目标是 了解恶性肿瘤与细胞分化之间的关系 状态。 N-myc 原癌基因的细胞表型和扩增是 调节神经母细胞瘤恶性潜能的两个因素。在 细胞系、N-myc 表达和恶性肿瘤受到显着影响 通过细胞分化状态。神经母细胞表达高水平 N-myc 细胞具有高度致瘤性，而非神经元 S 型细胞 来自同一亲本细胞系的 N-myc 含量明显较低 RNA/蛋白质并且是非致瘤性的。这两种细胞类型可能来自 第三种细胞类型，恶性程度更高的 I 型干细胞。而且， 实验诱导的细胞表型变化可以直接影响N- myc表达和转化状态。这些观察结果形成了 我们中心假设的基础：细胞分化状态决定 通过谱系特定以及环境因素，直接调节 N-myc 表达及其神经母细胞瘤的恶性潜力 细胞。 HuD 是调节 N-myc 表达的一种谱系特异性因子， 一种神经元特异性 RNA 结合蛋白。 HuD 出现在早期 神经发生并在所有神经元中表达。 HuD 结合 N-myc mRNA 并且，在反义 HuD 转染子中，其下调导致 N-myc 表达减少。该提案的两个目标是审查 这个假设的不同方面。目标 1 的重点是 确定 HuD 与 N-myc mRNA 相互作用的机制以及 从而调节其表达，并且作为推论，是否丧失 一个 HuD 等位基因是 N-myc 发展的关键因素 扩增和肿瘤侵袭性。目标 2 中提出的研究将 确定是否在人类中发现了明确特征的细胞类型 存在神经母细胞瘤细胞系（特别是 I 型干细胞） 在肿瘤中，如果是，它们的存在是否与肿瘤相关 阶段、攻击性或起源部位。获得的知识 肿瘤细胞的分化状态具有有利或 不良预后以及可直接影响细胞的因素 分化，从而导致恶性潜能，极有可能 在神经母细胞瘤的治疗中具有重要的应用。