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: 6514795
• 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/6514795
• 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