Cellular and Molecular Requirements for Medulloblastoma Tumorigenesis

髓母细胞瘤肿瘤发生的细胞和分子要求

• 批准号: 8194830
• 负责人: Desmond A Brown
• 金额: $ 1.93万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8194830
• 关键词: Ablation; Address; Affect; Architecture; Brain; Cell Cycle; Cell Line; Cells; Central Nervous System Neoplasms; Cerebellum; Chemotactic Factors; Child; Childhood; Cilia; Desmoplastic; Development; Disease; Engineering; Erinaceidae; Genetic Models; Human; Knockout Mice; Maintenance; Malignant Neoplasms; Mediating; Molecular; Morphology; Mouse Strains; Mus; Neuraxis; Neuroepithelial Neoplasms; Pathogenesis; Phosphotransferases; Population; Proteins; Recruitment Activity; Refractory; Regimen; Role; Site; Solid Neoplasm; Survivors; Testing; Therapeutic; Tumor-Derived; Work; cancer cell; cancer stem cell; improved; indexing; insight; medulloblastoma; mouse model; nerve stem cell; nestin protein; neurodevelopment; novel; novel diagnostics; precursor cell; progenitor; prognostic; public health relevance; relating to nervous system; response; small hairpin RNA; smoothened signaling pathway; stem; tool; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Medulloblastoma (MB) is a neuroepithelial tumor of the cerebellum and is the most common central nervous system (CNS) malignancy in children. While survival improved dramatically over the past two decades, approximately one-third remain refractory to treatment and current regimens result in long-term devastating sequelae. MBs, like several other tumors, are thought to be derived from a cell with stem-like features, so-called cancer stem cells (CSCs). Stem-like cancer cells have been demonstrated within several tumors of the CNS. However, it is unclear whether the tumors are derived from these cells, are simply recruited to the site by chemotactic factors released by the tumor stroma or whether cells within the tumor mass de-differentiate into these stem-like cells. The possibility that tumors are derived from stem-like populations has major implications for therapy since most anti- tumor regimens are geared towards elimination of cells with high proliferative index, which is not a feature of some particular classes of precursor cells such as the type B nestin+ precursor cells. In this study the cellular origins of MB will be evaluated through conditional ablation of nestin+ precursor cells in a mouse model of the disease. We will also evaluate the role of Ccrk in mouse neural development and the roles of BROMI and CCRK in the proliferation and tumorigenic potential of human desmoplastic MB cells. Our group recently showed that Bromi affects cilia morphology and Shh signaling and that it associates with and stabilizes Ccrk. This work will advance our understanding of the pathogenic mechanism of an important CNS tumor and may ultimately facilitate development of novel diagnostic, prognostic and therapeutic tools as well as enable deeper insight into the mechanistic details of the ubiquitous Shh signaling pathway. Moreover, since Shh misregulation occurs in a quarter of all human tumors and some aspects of MB pathogenesis may be generalizable to other CNS neoplasms, the results from this study may have far-reaching implications. PUBLIC HEALTH RELEVANCE: Medulloblastoma is the most common pediatric brain malignancy with dismal long-term survival and devastating sequelae in survivors. This project will address both cellular origins and molecular requirements for the development and maintenance of the disease. Results garnered from this work will deepen our understanding of medulloblastoma, potentially other CNS tumors and may reveal novel diagnostic, prognostic and therapeutic tools.

描述（由申请人提供）：髓母细胞瘤（MB）是一种小脑神经上皮肿瘤，是儿童中最常见的中枢神经系统（CNS）恶性肿瘤。虽然在过去二十年里生存率显着提高，但大约三分之一的患者仍然难以治疗，而目前的治疗方案会导致长期的毁灭性后遗症。与其他几种肿瘤一样，MB 被认为源自具有干细胞样特征的细胞，即所谓的癌症干细胞 (CSC)。干细胞样癌细胞已在中枢神经系统的几种肿瘤中得到证实。然而，目前尚不清楚肿瘤是否源自这些细胞，是否只是通过肿瘤基质释放的趋化因子招募到该部位，或者肿瘤块内的细胞是否去分化为这些干细胞样细胞。肿瘤源自干细胞样群体的可能性对于治疗具有重大意义，因为大多数抗肿瘤方案旨在消除具有高增殖指数的细胞，而这不是某些特定类别的前体细胞（例如B型巢蛋白+前体细胞）的特征。在这项研究中，MB 的细胞起源将通过在该疾病的小鼠模型中条件性消融巢蛋白+前体细胞来评估。我们还将评估 Ccrk 在小鼠神经发育中的作用以及 BROMI 和 CCRK 在人促纤维增生性 MB 细胞的增殖和致瘤潜力中的作用。我们的小组最近表明 Bromi 影响纤毛形态和 Shh 信号传导，并且它与 Ccrk 相关并稳定 Ccrk。这项工作将增进我们对重要中枢神经系统肿瘤致病机制的理解，并可能最终促进新型诊断、预后和治疗工具的开发，并能够更深入地了解普遍存在的 Shh 信号通路的机制细节。此外，由于四分之一的人类肿瘤中发生了Shh失调，并且MB发病机制的某些方面可能适用于其他中枢神经系统肿瘤，因此这项研究的结果可能具有深远的影响。 公共卫生相关性：髓母细胞瘤是最常见的儿科脑恶性肿瘤，其长期生存率很低，幸存者会留下毁灭性的后遗症。该项目将解决疾病发展和维持的细胞起源和分子要求。这项工作获得的结果将加深我们对髓母细胞瘤和其他潜在中枢神经系统肿瘤的理解，并可能揭示新的诊断、预后和治疗工具。