MOLECULAR MECHANISMS OF DIFFERENTIATION IN NEUROBLASTOMA

神经母细胞瘤是一种起源于神经脊部的恶性肿瘤。 儿童最常见的颅外实体瘤。自发分化-- NB对良性神经节细胞瘤的治疗在体内偶有发生。这 这一过程包括神经母细胞表型的丧失和 类似成熟神经节神经元的细胞。即使是在国家广播公司，也没有 完全成熟对良性神经节细胞瘤的组织学程度 成熟度直接影响肿瘤的临床行为， 因此，具有重要的临床意义。因为大多数人类神经母细胞瘤细胞 品系经历了形态和生化分化，以响应 包括维甲酸(RA)在内的多种药物，这是一种优秀的体外模型 可用于Nb分化的检查。这件事的重点是 研究将分离和鉴定NBS中的基因 在治疗180分钟后，表达被诱导或下调 差异筛选LA-N-5基因文库与RA的关系 用放射性标记的cDNAs探针研究RA处理NB细胞180分钟 从未经处理和RA处理的人NB细胞(LA-N-5.由科恩- 专注于表达的早期变化，这些基因可能是 实施分化过程，而不是基因 其产品与人的特定神经功能有关 分化的细胞可以被分离出来。其他NB细胞系，其中许多 已经在这个实验室中被建立和表征，随后将- 用与分化相关的序列进行探测以确定是否 这些克隆在RA处理后在其他N-myc扩增和 未放大的线条。此外，这些基因在原发灶中的表达 肿瘤及其表达水平与程度的关系 组织学分化程度和临床结果将会被确定。 最后，这些序列将被整合到表达载体中并 被重新引入人类神经母细胞。表达产物的生物学效应 然后将对受体细胞中的克隆进行分析。了解 NB分化的分子机制可能为深入了解Nb的分化提供依据。 与NB相关的分化调节改变。

Neuroblastoma (NB), a malignant neoplasm of neural crest origin, is the most common extracranial solid tumor in children. Spontaneous differentia- tion of NB to benign ganglioneuroma occurs occasionally in vivo. This process involves the loss of the neuroblast phenotype and the appearance of cells resembling mature ganglionic neurons. Even in NBs which do not mature completely to benign ganglioneuromas, the degree of histologic maturation directly influences the clinical behavior of the tumor and is, therefore, of clinical importance. Because most human neuroblastoma cell lines undergo morphologic and biochemical differentiation in response to a variety of gents including retinoic acid (RA), an excellent in vitro model for the examination of NB differentiation is available. The focus of this study will be to isolate and characterize the genes in NBs in which expression is either induced or down-regulated 180 minutes after treatment with RA by differentially screening a cDNA library constructed from LA-N-5 NB cells treated with RA for 180 minutes with radiolabeled cDNA probes prepared from untreated and RA-treated human NB cells (LA-N-5. By con- centrating on early changes in expression, genes which may be necessary for the implementation of the differentiation process rather than the genes whose products are associated with the specific neural features of the differentiated cell may be isolated. Other NB cell lines, many of which have been established an characterized in this laboratory, will subsequent- ly be probed with the differentiation related sequences to determine if these clones are expressed after RA treatment in other N-myc amplified and unamplified lines. In addition, the expression of these genes in primary tumors and the relationship between the levels of expression and the degree of histologic differentiation, and clinical outcome will be determined. Finally, these sequences will be incorporated into expression vectors and introduced back into human NB cells. Biological effects of the expressed clones in recipient cells will then be analyzed. Understanding the molecular mechanisms of NB differentiation may provide insight into the altered regulation of differentiation associated with NB.