Role of Neurotrophin Receptors in Neuroblastoma

神经营养蛋白受体在神经母细胞瘤中的作用

• 批准号: 6771797
• 负责人: DARRELL J YAMASHIRO
• 金额: $ 25.75万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6771797
• 关键词: Adenoviridae; angiogenesis; athymic mouse; autocrine; cell differentiation; fibroblasts; growth factor receptors; hypoxia; immunocytochemistry; metastasis; mitogen activated protein kinase; neoplastic growth; neuroblastoma; neurotrophic factors; oncoproteins; paracrine; transfection /expression vector; vascular endothelial growth factors

DESCRIPTION: (Adapted from the investigator's abstract) Neuroblastoma has a wide spectrum of clinical behavior, with tumors regressing spontaneously in infants, to widely metastatic disease and poor outcome despite intensive chemotherapy and bone marrow transplantation. The biological mechanism for these disparate clinical behaviors is likely to involve the neurotrophin receptors TrkA, TrkB, and TrkC, and their respective ligands, NGF, BDNF, and NT3. Favorable neuroblastomas express TrkA and TrkC, but not NGF or NT3. In contrast, unfavorable, metastatic neuroblastomas express TrkB and BDNF. Based on these observations we have proposed a model in which TrkA and TrkC promote favorable neuroblastoma by inducing neuronal d~(ferentiation, while an autocrine loop of TrkB and BDNF promotes unfavorable neuroblastoma by enhancing tumor growth, cell survival, and metastasis. In support of this model, studies have shown that TrkA and TrkC can induce neuronal differentiation, that TrkB can increase cell survival, stimulate cell invasiveness, and is chemoprotective. TrkB can also increase the expression of vascular endothelial growth factor (VEGF), suggesting that TrkB can induce angiogenesis, a critical step in tumor proliferation and metastases. The overall goal of this grant to obtain in vivo evidence for the Trk-NBL model. Our experiments will focus on TrkB and the autocrine/paracrine loop formed with BDNF, with the results compared with TrkC and NT3. For the in vivo studies we will use a xenograft model in the nude mouse that we have developed in our laboratory that produces large primary tumors and metastases to lung, liver, or bone marrow. Aim 1. We hypothesize that in vivo, TrkB promotes cell survival, proliferation, and metastases, while TrkC promotes differentiation. We will compare the ability of TrkB and TrkC to promote cell survival, tumor growth, metastases, differentiation, and protect against chemotherapy in vivo. Aim 2. We hypothesize that an autocrine or paracrine loop of BDNF/TrkB or NT3/TrkC promotes cell survival and differentiation. We will determine if autocrine expression of BDNF or NT3 in neuroblastoma cell lines or fibroblasts promotes differentiation or survival. Aim 3. We hypothesize that Trk receptors regulate angiogenesis in neuroblastoma. We will determine if TrkB and TrkC regulate the expression of VEGF and determine the signal pathways involved. We will determine if TrkB and TrkC protect neuroblastoma against hypoxia induced by anti-VEGF agents. By systematically comparing TrkB with TrkC in vivo, these studies will allow us to determine the validity of the Trk-NBL model.

描述：（改编自研究者的摘要）神经母细胞瘤具有 广泛的临床行为，肿瘤在 婴儿，尽管进行了强化治疗，但仍会出现广泛转移性疾病和不良结果 化疗和骨髓移植。其生物学机制为 这些不同的临床行为可能与神经营养素有关 受体 TrkA、TrkB 和 TrkC 及其各自的配体 NGF、BDNF 和 NT3。有利的神经母细胞瘤表达 TrkA 和 TrkC，但不​​表达 NGF 或 NT3。在 相反，不利的转移性神经母细胞瘤表达 TrkB 和 BDNF。基于 根据这些观察结果，我们提出了一个模型，其中 TrkA 和 TrkC 促进 通过诱导神经元 d~（发酵，同时 TrkB 和 BDNF 的自分泌环通过增强 肿瘤生长、细胞存活和转移。为了支持这个模型，研究 研究表明，TrkA 和 TrkC 可以诱导神经元分化，TrkB 可以增加细胞存活率，刺激细胞侵袭性， 化学保护作用。 TrkB还可以增加血管内皮细胞的表达 生长因子 (VEGF)，表明 TrkB 可以诱导血管生成，这是一个关键的 肿瘤增殖和转移的一步。本次资助的总体目标是 获得 Trk-NBL 模型的体内证据。我们的实验将集中于 TrkB 和 BDNF 形成的自分泌/旁分泌环，结果 与 TrkC 和 NT3 相比。对于体内研究，我们将使用异种移植物 我们在实验室开发的裸鼠模型可以产生 大型原发肿瘤和转移至肺、肝或骨髓。目标 1. 我们 假设在体内，TrkB 促进细胞存活、增殖和 转移，而 TrkC 促进分化。我们将比较以下人员的能力 TrkB 和 TrkC 促进细胞存活、肿瘤生长、转移、 分化，并防止体内化疗。目标 2. 我们 假设 BDNF/TrkB 或 NT3/TrkC 的自分泌或旁分泌环 促进细胞存活和分化。我们将确定是否自分泌 神经母细胞瘤细胞系或成纤维细胞中 BDNF 或 NT3 的表达促进 分化或生存。目标 3. 我们假设 Trk 受体调节 神经母细胞瘤中的血管生成。我们将确定 TrkB 和 TrkC 是否调节 VEGF 的表达并确定所涉及的信号通路。我们将 确定 TrkB 和 TrkC 是否可以保护神经母细胞瘤免受由 抗VEGF剂。通过在体内系统地比较 TrkB 和 TrkC，这些 研究将使我们能够确定 Trk-NBL 模型的有效性。