GROWTH REGULATING GENES IN PRIMITIVE NEUROECTODERMAL TUMORS

髓母细胞瘤是儿童最常见的恶性脑肿瘤。它被认为起源于发育中的小脑中的颗粒细胞神经元细胞神经元的祖细胞，并且被归类为原始神经外胚层肿瘤。大约一半的儿童和年轻人患有这种疾病，手术和辅助治疗后存活超过10年。其他人在面对同样的治疗时复发并死亡。几年前，我们和我们的同事发现了髓母细胞瘤的预后指标。我们发现“标准风险”髓母细胞瘤表达高水平的编码神经营养素-3受体蛋白TrkC的mRNA。“高危”髓母细胞瘤表达低水平的trkC。我们在这里描述的实验就是基于这一观察。我们有三个具体目标。第一个目的是建立trkC在标准风险与高风险髓母细胞瘤中过度表达的细胞基础。标准风险肿瘤中表达trkC mRNA的细胞比例是否更高，或者这些肿瘤中的细胞每个细胞表达更多的trkC mRNA？使用原位杂交和免疫组织化学测定的定量分析将被用来解决这个问题。这将阐明高和低trk C肿瘤是否代表两种不同类型的髓母细胞瘤或共同的髓母细胞瘤祖细胞演变的连续阶段。第二个具体目标是确定是否可以与TrkC蛋白本身或与TrkC信号传导功能进行预后相关。我们将使用磷酸酪氨酸定向抗体来确定TrkC信号传导功能在体内标准风险肿瘤中是否是活性的。这将是了解TrkC激活是否抑制肿瘤生长的重要一步。第三个具体目标是确定在标准风险与高风险髓母细胞瘤中哪些其他基因与trk C一起协同上调沿着。 为此，我们将使用大量的标准和高风险髓母细胞瘤来筛选由Stiles博士基于其在高风险和标准风险肿瘤中的差异表达而分离的克隆。总之，这里概述的研究将提供一个基础，了解分子属性，使一些患者的髓母细胞瘤治愈他们的疾病。

Medulloblastoma is the most common malignant brain tumor of childhood. It is thought to originate from the progenitors of granule cell neurons cell neurons in the developing cerebellum and it is classified as a primitive neuroectodermal tumor. About half the children and young adults with this disease survive longer than 10 years following surgery and adjuvant therapy. The others relapse and die in the face of identical treatment. Several years ago, we and our colleagues discovered a prognostic indicator for medulloblastoma. We showed that "standard risk" medulloblastomas express high levels of mRNA encoding the neurotrophin-3 receptor protein TrkC. The "high risk" medulloblastomas express low levels of trkC. The experiments we describe here are based upon this observation. We have three specific aims. The first aim is to establish the cellular basis for trkC over-expression in standard risk versus high risk medulloblastomas. Do standard risk tumors contain a greater percentage of cells that express trkC mRNA, or do the cells within these tumor express more trkC mRNA per cell? Quantitative analysis using in situ hybridization and immunohistochemical assays will be used to address this question. This will elucidate whether high and low trk C tumors represent two distinct types of medulloblastoma or sequential stages in the evolution of a common medulloblastoma progenitor. The second specific aim is to determine whether a prognostic correlation can be made with TrkC protein per se or with TrkC signaling functions. We will use phosphotyrosine directed antibodies to determine whether TrkC signaling functions are active in standard risk tumors in vivo. This will be an important step in learning whether activation of TrkC inhibits tumor growth. The third specific aim is to determine which other genes are coordinately up-regulated along with trk C in standard risk versus high risk medulloblastomas. Towards this end we will use a large cohort of standard and high risk medulloblastomas to screen the clones isolated by Dr. Stiles based on their differential expression in a high risk and standard risk tumor. Taken together the studies outlined here will provide a basis for understanding molecular attributes that enable some patients with medulloblastoma to be cured of their disease.