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。患髓母细胞瘤的儿童中几乎有一半死于髓母细胞瘤，幸存者往往会因为治疗而出现严重的副作用。治疗髓母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了解。关于髓母细胞瘤病因学的一个关键问题是它起源的细胞。肿瘤细胞的形态及其在小脑表面的位置导致推测肿瘤起源于颗粒细胞前体(GCP)，这是一种仅产生颗粒神经元的限制性神经前体细胞。另一方面，最近的研究表明，髓母细胞瘤表达干细胞标记物，并可以分化为神经元和神经胶质细胞，这表明其中一些肿瘤可能来自多潜能神经干细胞(NSCs)。具有NSC表型的细胞也被认为代表“癌症干细胞”，这是一种对传统疗法具有抵抗力的细胞，对体内肿瘤的长期生长和繁殖至关重要。起源细胞和肿瘤干细胞可能有关联，也可能没有关联，但识别它们中的每一个对于理解和治疗髓母细胞瘤具有重要意义。我们的目标是确定髓母细胞瘤的起源细胞(“肿瘤起始细胞”)和癌症干细胞(“肿瘤增殖细胞”)，这些细胞是由Sonic Hedgehog-Patch信号通路突变引起的。具有这一途径突变的人类对髓母细胞瘤的易感性增加。此外，打补丁的突变小鼠患上类似人类髓母细胞瘤的肿瘤，是治疗这种疾病的一个有价值的模型。我们的初步研究表明，斑块相关肿瘤的起源细胞是颗粒细胞前体，这种细胞类型不仅是肿瘤启动所必需的，也是肿瘤生长所必需的。我们现在建议确定具有启动肿瘤能力的GCP亚群，以及能够在移植后独一无二地繁殖肿瘤的肿瘤细胞亚群。鉴定这些细胞将提供对转化机制的重要洞察，并将帮助我们开发和测试靶向髓母细胞瘤的新方法。 公共卫生相关性：确定髓母细胞瘤的起源细胞将使我们能够将肿瘤细胞与正常细胞进行比较，从而确定肿瘤细胞的关键差异和脆弱性。此外，最近的研究表明，与起源细胞相似的细胞可能在成熟肿瘤中持续存在(作为“癌症干细胞”)，并可能是这些肿瘤在体内繁殖的关键。鉴定这些细胞可能会让我们开发出更有效的方法来根除肿瘤。

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.