Stem Cells, Progenitors, and the Origin of Medulloblastoma

描述（申请人提供）：髓母细胞瘤是儿童最常见的恶性脑肿瘤。几乎有一半患有成神经管细胞瘤的儿童死于此，幸存者通常会因治疗而产生严重的副作用。治疗成神经管细胞瘤的改进方法可能来自对这种疾病的细胞和分子基础的更深入的了解。髓母细胞瘤病因学的一个关键问题是它起源于哪个细胞。肿瘤细胞的形态及其在小脑表面的位置导致人们猜测肿瘤起源于颗粒细胞前体（GCPs），这是一种仅产生颗粒神经元的限制性神经祖细胞。另一方面，最近的研究表明，髓母细胞瘤表达干细胞标记物，并可分化为神经元和胶质细胞，这表明其中一些肿瘤可能起源于多能神经干细胞（NSCs）。具有NSC表型的细胞也被认为代表“癌症干细胞”，这些细胞对常规疗法具有抗性，对肿瘤在体内的长期生长和繁殖至关重要。起源细胞和癌症干细胞可能相关，也可能无关，但识别它们中的每一个对于理解和治疗成神经管细胞瘤具有重要意义。我们的目标是鉴定由Sonic hedgehog-Patched信号通路突变引起的成神经管细胞瘤的起源细胞（“肿瘤起始细胞”）和癌症干细胞（“肿瘤增殖细胞”）。具有该通路突变的人对成神经管细胞瘤的易感性增加。此外，补丁突变小鼠产生的肿瘤类似于人类成神经管细胞瘤，代表了一种有价值的疾病模型。我们的初步研究表明，斑块相关肿瘤的起源细胞是一种颗粒细胞前体细胞，这种细胞类型不仅是肿瘤发生所必需的，而且也是肿瘤增殖所必需的。我们现在建议鉴定富含启动肿瘤能力的gcp亚群，以及移植后具有独特肿瘤增殖能力的肿瘤细胞亚群。鉴定这些细胞将提供对转化机制的关键见解，并将帮助我们开发和测试针对成神经管细胞瘤的新方法。

DESCRIPTION (provided by applicant): Medulloblastoma is the most common malignant brain tumor in children. Almost half the children who develop medulloblastoma die from it, and survivors often develop severe side effects as a result of the treatment. Improved approaches to treating medulloblastoma are likely to come from a deeper understanding of the cellular and molecular basis of the disease. One critical question about the etiology of medulloblastoma is the cell from which it originates. The morphology of tumor cells and their location on the surface of the cerebellum have led to speculation that the tumors arise from granule cell precursors (GCPs), restricted neural progenitors that give rise only to granule neurons. On the other hand, recent studies have shown that medulloblastomas express stem cell markers and can differentiate into both neurons and glia, suggesting that some of these tumors may arise from multipotent neural stem cells (NSCs). Cells with an NSC phenotype have also been suggested to represent "cancer stem cells", cells that are resistant to conventional therapies and critical for the long-term growth and propagation of tumors in vivo. The cell of origin and the cancer stem cell may or may not be related, but identifying each of them has important implications for understanding and treating medulloblastoma. Our goal is to identify the cell of origin ("tumor-initiating cell") and the cancer stem cell ("tumor-propagating cell") for medulloblastomas resulting from mutations in the Sonic hedgehog-Patched signaling pathway. Humans with mutations in this pathway have an increased susceptibility to medulloblastoma. Moreover, patched mutant mice develop tumors that resemble human medulloblastoma, and represent a valuable model for the disease. Our preliminary studies suggest that the cell of origin in patched- associated tumors is a granule cell precursor, and that this cell type is required not only for tumor initiation but also for tumor propagation. We now propose to identify subsets of GCPs that are enriched for the ability to initiate tumors, and subsets of tumor cells that are uniquely capable of propagating tumors following transplantation. Identifying these cells will provide critical insight into the mechanisms of transformation, and will help us develop and test novel approaches to targeting medulloblastoma. PUBLIC HEALTH RELEVANCE: Identifying the cell of origin for medulloblastoma will allow us to compare tumor cells to their normal counterparts, so that key differences and vulnerabilities of tumor cells can be identified. In addition, recent studies suggest that cells resembling the cell of origin may persist in mature tumors (as "cancer stem cells"), and may be critical for propagating these tumors in vivo. Identifying these cells may allow us to develop more effective methods for eradicating the tumor.