HUMAN NEUROBLASTOMA CELL TRANSDIFFERENTIATION

人神经母细胞瘤细胞转分化

• 批准号: 3182081
• 负责人: JUNE L. BIEDLER
• 金额: $ 20.68万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3182081
• 关键词: Ewing's tumor; athymic mouse; cancer registry /resource; cell transformation; cell type; child (0-11); clone cells; cytoskeleton; epithelioma; extracellular matrix; gene expression; growth factor receptors; human tissue; immunocytochemistry; in situ hybridization; laboratory mouse; natural gene amplification; neoplasm /cancer genetics; neoplasm /cancer remission /regression; neoplastic cell; neoplastic transformation; neural crest; neuroblastoma; oncogenes; pediatric neoplasm /cancer; radionuclide double label; surface antigens

Current therapeutic regimens have failed to decrease the high (80 to 90%) mortality rate of neuroblastoma, indicating the need for new therapeutic approaches. Crucial to any approach to therapy is the knowledge of the cell biology of neuroblastoma. One important characteristic of this tumor, both in the patient and in tissue culture, is its marked cellular heterogeneity. Previous and current studies show that many neuroblastoma cell lines comprise two or more cell types: neuroblastic (N) cells which contain neurofilaments and noradrenergic properties (enzymes, uptake mechanisms, and receptors) and substrate-adherent (S), non-neuronal cells with enzymes, intermediate filaments, cell surface antigens, and extracellular matrix (ECM) proteins characteristiC Of embryonic mesectodermal (glial/melanocytic/meningeal) cells. Recently identified intermediate (I) cells share properties of both N and S cells and may represent either a stem cell or a transitional cell between N and S. Important findings related to this cellular heterogeneity are: (i) N and S cells undergo bidirectional phenotypic interconversion (transdifferentiation); (ii) morphological, biochemical, and cell surface antigen changes in N/S interconversion are tightly coordinated, suggesting that this process is controlled by one or very few regulatory genes; and (iii) N cells are highly tumorigenic whereas S cells are non-tumorigenic. Two other pediatric tumors, Ewing's sarcoma and peripheral neuroepithelioma, appear neuroectodermal in origin and comprise N- and S-like cells. Proposed aims are to: (1) quantitate expression (and gene copy number) in N and S cells of oncogenes N-myc and Ha-ras, EGF and NGF receptor and TGF alpha, cell surface antigens, and gangliosides by molecular hybridization and/or immunochemical techniques as a means of distinguishing correlates of both differentiation state and transformation state; (2) examine effects of several soluble-, growth and differentiation factors (e.g., retinoic acid and cyclic AMP) as a means of experimentally inducing differentiation; (3) study t-role of the ECM and cell-cell interactions in N/S interconversion, in an attempt to identify extrinsic signal(s) regulating differentiation or transdifferentiation in clonal cell lines; and (4) determine whether tumors in vivo contain counterparts of the S observed in cell culture to evaluate the prevalence of N/S transdifferentiation in cal neuroblastoma. The current aims represent a continuing effort to define mechanisms underlying transdifferentiation and transformation in human neuroblastoma.

当前的治疗方案未能降低高（80％至90％） 神经母细胞瘤的死亡率，表明需要新的治疗 方法。对任何治疗方法至关重要的是细胞的知识 神经母细胞瘤的生物学。该肿瘤的一个重要特征，两者都 在患者和组织培养中，是其明显的细胞异质性。 以前和当前的研究表明许多神经母细胞瘤细胞系 包括两种或多种细胞类型：包含的神经细胞（n）细胞 神经丝和去甲肾上腺素能特性（酶，摄取机制， 和受体）和底物粘附，具有酶的非神经元细胞， 中间细丝，细胞表面抗原和细胞外基质 （ECM）胚胎中胚层的蛋白质特征 （神经胶质/黑素/脑膜/脑膜）细胞。最近确定的中级（i） 细胞共享N和S细胞的特性，并且可能代表A 干细胞或N和S之间的过渡细胞 与这种细胞异质性有关的是：（i）N和S细胞经历 双向表型相互转换（转分化）； （ii） N/S的形态学，生化和细胞表面抗原变化 互换紧密地协调，表明此过程是 由一个或几个调节基因控制； （iii）n个细胞是 高度肿瘤的细胞是非肿瘤的。 另外两个 小儿肿瘤，尤因的肉瘤和周围神经上皮瘤出现 神经皮质的起源，包括N-和S样细胞。 拟议的目标 为：（1）N和S细胞中量化表达（和基因拷贝数） ONCEGONES N-MYC和HA-RAS，EGF和NGF受体以及TGF Alpha，细胞 表面抗原，以及通过分子杂交和/或 免疫化学技术是区分两者相关的一种手段 分化状态和转变状态； （2）检查 几种可溶性，生长和分化因子（例如视黄酸 和环状AMP）作为实验诱导分化的一种手段； （3） 在N/S互传中的ECM和细胞 - 细胞相互作用的研究T-ROLE， 试图识别调节分化或 克隆细胞系中的差异； （4）确定肿瘤是否 体内包含在细胞培养中观察到的S的对应物来评估 Cal神经母细胞瘤中N/S转分化的患病率。这 当前的目标代表了定义基本机制的持续努力 人神经母细胞瘤的转变和转化。