NEUROTROPHIN AND TRK EXPRESSION IN MEDULLOBLASTOMA AND NEUROBLASTOMA

神经母细胞瘤是一种源于神经脊部的肿瘤，表达 TrkA、TrkB和TrkC编码的酪氨酸激酶受体 发展。这些受体与神经营养因子NGF、BDNF、 和NT-3。我们已经证明了这一有利条件 神经母细胞瘤表达TrkA和TrkC，而不表达N-myc 扩增的神经母细胞瘤表达TrkB。在髓母细胞瘤中， TrkC的表达与更有利的预后相关。 这些研究导致了我们的假设，即TrkA的激活 和/或TrkC诱导分化，导致有利的 结果，而TrkB的激活对生存或 不良肿瘤的生长。支持这一概念的是研究 对神经母细胞瘤表现出明显不同的反应 神经营养素加成--有利的原发肿瘤对NGF的反应 BDNF促进细胞生长/存活时的分化 台词。我们的假设提出的一个重要问题是，如何 Trk家族的不同成员推动着相反的命运 分化和生长。这项提议的目标是 了解TrkB和TrkC在神经母细胞瘤和 目的：探讨髓母细胞瘤的发病机制。 哪些相似的受体促进了不同的结果。具体来说， 我们将确定TrkB受体在不良反应中的作用 神经母细胞瘤中信号转导通路的研究 表达内源性TrkB的细胞系。我们将确定 信号中间产物SHC、PI3的激活模式 激酶和PLC-Gamma1，并确定是否有信号通路参与 PC12细胞分化--ERK和ERK激活延长 BDNF可诱导SNT--的磷酸化。我们将决定 TrkB或TrkC的过度表达(主要表达于 良性肿瘤)，调节分化或细胞生长。我们 将研究TrkC受体在有利的 神经母细胞瘤中神经营养因子附加作用的研究 对原代培养有利的神经母细胞瘤停止培养。 信号转导通路将在足够的时候被检查 纸巾是可用的。我们计划在#年进行平行研究。 髓母细胞瘤细胞系。我们将确定脑源性神经营养因子的作用 和NT-3，我们将开发出能够 通过以下方式识别TrkA、TrkB和TrkC 免疫组织化学。这些研究的圆满完成 可能为我们提供重要的洞察力 激活不同的Trk家族受体。此外，我们的 结果应提供有关以下方面的重要信息 TrkB和TrkC在神经母细胞瘤和神经母细胞瘤中的表达 从Trk类型看髓母细胞瘤和髓母细胞瘤 表达可能有助于预测结果并指导治疗 病人。

Neuroblastomas are neural crest derived tumors that express tyrosine kinase receptors encoded by TrkA, TrkB, and TrkC during development. These receptors bind to the neurotrophins NGF, BDNF, and NT-3, respectively. We have shown that favorable neuroblastoma express TrkA and TrkC, while unfavorable, N-myc amplified neuroblastomas express TrkB. In medulloblastomas, high expression of TrkC is associated with more favorable outcome. These studies have lead to our hypothesis that activation of TrkA and/or TrkC induces differentiation leading to a favorable outcome, while activation of TrkB is critical to the survival or growth of unfavorable tumors. Supporting this concept are studies in neuroblastoma that show a distinct difference in response to neurotrophin addition--favorable primary tumors respond to NGF by differentiation while BDNF promotes growth/ survival in cell lines. An important question raise by our hypothesis is how do different members of the Trk family promote the opposite fates of differentiation and growth. The goals of this proposal are to understand the roles of TrkB and TrkC in neuroblastoma and medulloblastoma pathogenesis and to elucidate the mechanism by which similar receptors promote different outcomes. Specifically, we will determine the role of TrkB receptors in unfavorable neuroblastomas by examining the signal transduction pathways in cell lines expressing endogenous TrkB. We will determine the activation patterns of the signaling intermediates, SHC, PI3 kinase, and PLC-gamma1, and determine if pathways involved in differentiation in PC12 cells--prolonged activation of ERK and phosphorylation of SNT--are induced by BDNF. We will determine whether the overexpression of TrkB or TrkC (expressed primarily in favorable tumors), mediates differentiation or cell growth. We will examine the role of TrkC receptors in favorable neuroblastomas by determining the effect of neurotrophin addition and withdrawal on primary cultures of favorable neuroblastomas. Signal transduction pathways will be examined when sufficient tissue is available. We plan to conduct parallel studies in medulloblastoma cell lines. We will determine the effect of BDNF and NT-3 and we will develop monoclonal antibodies that can specifically recognize TrkA, TrkB and TrkC by immunohistochemistry. The successful completion of these studies may provide important insights into the selective effects of activating the different Trk family receptors. Furthermore, our results should provide important information about the role of TrkB and TrkC in different subsets of neuroblastomas and medulloblastomas and medulloblastomas by their pattern of Trk expression may help predict outcome and guide therapy for these patients.