Role of Gastrin-releasing Peptide in Neuroblastoma

胃泌素释放肽在神经母细胞瘤中的作用

• 批准号: 6692147
• 负责人: DAI H. CHUNG
• 金额: $ 33.53万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6692147
• 关键词: Role; Gastrin; releasing; Peptide; Neuroblastoma

DESCRIPTION (provided by applicant): Neuroblastoma is the most common extracranial solid tumor in infants and children, and accounts for more than 15% of cancer-related deaths in children. Despite recent advances in combined modality treat-ment, the overall mortality for all stages of tumors remains significant at 50%. As a neuroendocrine tumor, neuroblastomas can produce various gastrointestinal (GI) hormones and the amount of peptide expression has been associated with the clinical tumor behavior suggesting a potential role for gut )eptides as autocrine growth factors. Gastrin-releasing peptide (GRP) is a gut/neuropeptide that stim-Jlates the growth of normal and neoplastic tissues and has also been found to be an autocrine growth factor for some cancers. Our studies have identified an increased expression of GRP-receptors (GRP-R) in more aggressive undifferentiated neuroblastomas. Additionally, we have found that GRP functionally couples to GRP-R to stimulate tumor growth, suggesting a role of GRP as an autocrine growth factor for neuroblastomas. Furthermore, we have demonstrated that phosphatidylinositol 3-kinase (PI3-K) pathway, an important signal transduction pathway involved in cell survival, regulates GRP-R expression in neuroblastoma. Based on our findings, the central hypothesis of this proposal is that GRP stimulates the growth of neuroblastoma cells through the activation of GRP-R, which in turn is regulated by PI3-K signal transduction pathway. To examine this, we have planned the following Specific Aims: 1) to further characterize the expression of GRP-R and its ligand GRP in human neuroblastomas, 2) to delineate the molecular mechanisms regulating GRP-R expression in neuroblastomas, 3) to determine the effects of the GRP/GRP-R pathway on neuroblastoma growth. Understanding the factors regulating GRP/GRP-R expression will provide novel and important information regarding the potential rote of GRP as an autocrine growth factor for neuroblastomas. This information is clinically significant because either expression of GRP-R or GRP may act as a tumor marker to predict tumor aggressiveness or potential response to therapy. Furthermore, a better understanding of the cellular mechanisms and signaling pathways regulating neuroblastoma cell growth could potentially lead to the development of novel therapeutic aqents as adjuvant treatment for this devastating disease.

描述（由申请人提供）：神经母细胞瘤是婴儿和儿童中最常见的颅外实体瘤，占儿童癌症相关死亡的 15% 以上。尽管最近在联合治疗方面取得了进展，但所有阶段肿瘤的总体死亡率仍然高达 50%。作为一种神经内分泌肿瘤，神经母细胞瘤可以产生各种胃肠道（GI）激素，并且肽表达量与临床肿瘤行为相关，表明肠肽作为自分泌生长因子的潜在作用。胃泌素释放肽 (GRP) 是一种肠道/神经肽，可刺激正常组织和肿瘤组织的生长，并且还被发现是某些癌症的自分泌生长因子。我们的研究发现，更具侵袭性的未分化神经母细胞瘤中 GRP 受体 (GRP-R) 的表达增加。此外，我们发现 GRP 在功能上与 GRP-R 偶联以刺激肿瘤生长，这表明 GRP 作为神经母细胞瘤的自分泌生长因子的作用。此外，我们还证明磷脂酰肌醇3激酶（PI3-K）途径是参与细胞存活的重要信号转导途径，可调节神经母细胞瘤中GRP-R的表达。根据我们的研究结果，该提案的中心假设是GRP通过激活GRP-R刺激神经母细胞瘤细胞的生长，而GRP-R又受到PI3-K信号转导途径的调节。为了研究这一点，我们计划了以下具体目标：1) 进一步表征 GRP-R 及其配体 GRP 在人神经母细胞瘤中的表达，2) 描述调节神经母细胞瘤中 GRP-R 表达的分子机制，3) 确定GRP/GRP-R 通路对神经母细胞瘤生长的影响。了解调节 GRP/GRP-R 表达的因素将为 GRP 作为神经母细胞瘤自分泌生长因子的潜在机制提供新颖且重要的信息。该信息具有临床意义，因为 GRP-R 或 GRP 的表达都可以作为肿瘤标志物来预测肿瘤的侵袭性或对治疗的潜在反应。此外，更好地了解调节神经母细胞瘤细胞生长的细胞机制和信号通路可能会导致开发新型治疗剂作为这种破坏性疾病的辅助治疗。