MOLECULAR BIOLOGY OF PEDIATRIC TUMORS

儿科肿瘤的分子生物学

• 批准号: 6290784
• 负责人: LEE J. HELMAN
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290784
• 关键词: Ewing's tumor; cell growth regulation; cell line; child (0-11); chromosome translocation; clinical research; gene expression; human subject; insulinlike growth factor; laboratory mouse; molecular pathology; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; neoplastic transformation; osteosarcoma; pediatric neoplasm /cancer; rhabdomyosarcoma; sarcoma; transcription factor

We have continued to focus on the role of insulin-like growth factors (IGFs) and tumor specific translocations in the pathogenesis of pediatric sarcomas, specifically rhabdomyosarcomas (RMS), Ewings sarcomas/PNET (Ewings family of tumors EFT), and osteogenic sarcomas (OS). We have recently confirmed that the fusion protein PAX3-FKHR generated by the tumor specific translocation of alveolar RMS leads to overexpression of IGF2 and an IGF binding protein (IGFBP-5) critical for IGF signaling. We have determined that the mechanism of PAX3-FKHR induced increase in IGF2 expression is indirect, since there is no evidence of direct binding to the region of the IGF2 promoter that is positively regulated by co-transfection studies. The mechanism and effect of increased IGFBP-5 expression due to PAX3-FKHR is currently under investigation. We have continued to utilize C2 mouse myoblasts overexpressing IGF2 to determine specific consequences of IGF2 overexpression in a muscle background. We have identified cabonic anhydrase 6 as overexpressed in C2 cells overexpressing IGF2 and are currently working to determine the significance of this finding. We are hoping to further analyze C2 cells with high IGF2 expression compared to normal C2 cells using cDNA microarray analysis. Recently, we have confirmed the overexpression of acetylcholine receptor gamma subunit in human rhabdomyosarcomas and are working to determine whether this can be exploited clinically. Finally, we are beginning to collaborate on a genetic model of rhabdomyosarcoma in mice, and have found that this model predicts abnormalities in the p16-CDK-4-cylcin D-Rb pathway in these tumors and have confirmed such abnormalities in human tumor specimens. We have now firmly established a mouse orthotopic model of osteosarcoma with spontaneous metastases, and are using cDNA microarray analyses to identify genetic determinants of metastasis in this model. We also continue to explore the potential role of combining growth hormone inhibition with chemotherapy in canine osteosarcoma, studying the hypothesis that lowering IGFI levels prior to cytotoxic chemotherapy will lead to increased apoptosis in tumor tissue dependent on IGFI for survival. - cell cycle, IGF-I receptor, IGF-I, IGF-2, Ewing's sarcoma family of tumors (ESFT), rhabdomyosarcoma, - Human Subjects: Minor under 18 Years Old & Human Tissues, Fluids, Cells, etc.

我们继续关注胰岛素样生长因子（IGF）和肿瘤特异性易位在小儿肉瘤发病机理中的作用，特别是横纹肌肉瘤（RMS），Ewings肉瘤/PNET（肿瘤家族）和OSTEEGENIC SARMAMACAS（OSTEEGENIC SARMAMAS（OS）（OS）。我们最近证实，肺泡RMS的肿瘤特异性转运产生的融合蛋白PAX3-FKHR导致IGF2的过表达和IGF结合蛋白（IGFBP-5）对IGF信号至关重要。我们已经确定PAX3-FKHR的机理诱导IGF2表达的增加是间接的，因为没有证据表明与IGF2启动子的区域直接结合，而IGF2启动子的区域受共转染研究的积极调节。目前正在研究由于PAX3-FKHR引起的IGFBP-5表达增加的机制和影响。我们继续利用过表达IGF2的C2小鼠成肌细胞来确定在肌肉背景下IGF2过表达的特定后果。我们已经确定Cabonic赤霉素6在过表达IGF2的C2细胞中过表达，目前正在努力确定该发现的重要性。我们希望使用cDNA微阵列分析与正常C2细胞相比，进一步分析具有高IGF2表达的C2细胞。最近，我们已经证实了人类横幅性肉瘤中乙酰胆碱受体伽马亚基的过表达，并正在努力确定是否可以在临床上利用这一点。最后，我们开始在小鼠的横纹肌肉瘤的遗传模型上进行合作，并发现该模型预测了这些肿瘤中P16-CDK-4-甲苯蛋白D-RB途径的异常，并证实了人类肿瘤标本中的这种异常。现在，我们已经牢固地建立了一种具有自发转移的骨肉瘤的小鼠原位模型，并正在使用cDNA微阵列分析来鉴定该模型中转移的遗传决定因素。我们还继续探索犬骨肉瘤中生长激素抑制与化学疗法相结合的潜在作用，研究假说，即在细胞毒性化学疗法之前降低IGFI水平将导致依赖IGFI的肿瘤组织中的细胞凋亡增加。 - 细胞周期，IGF-I受体，IGF-I，IGF-2，Ewing的肉瘤家族（ESFT），横纹肌肉瘤，人类受试者：未满18岁的次要年龄和人类组织，人类组织，液体，液体，细胞等。