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: 6572829
• 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/6572829
• 关键词: animal tissue; autocrine; biological signal transduction; cell growth regulation; cellular pathology; enzyme inhibitors; gastrin releasing peptide; gastrointestinal hormones; gene expression; growth factor; human tissue; immunocytochemistry; ionophores; molecular pathology; neoplastic cell; neoplastic growth; neuroblastoma; neuropeptide receptor; phosphatidylinositol 3 kinase; protein structure function; receptor expression; transcription factor

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。尽管联合态度治疗的联合近期进展，但肿瘤所有阶段的总体死亡率仍然显着为50％。作为神经内分泌肿瘤，神经母细胞瘤可以产生各种胃肠道（GI）激素，并且肽表达的量与临床肿瘤行为有关，这表明肠道的潜在作用）eptides作为自分泌生长因子。胃蛋白释放肽（GRP）是一种肠道/神经肽，它可以刺激正常和肿瘤组织的生长，并且也被发现是某些癌症的自分泌生长因子。我们的研究确定了在更具侵略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伴侣刺激肿瘤生长，这表明GRP是神经母细胞瘤的自分泌生长因子的作用。此外，我们已经证明，磷脂酰肌醇3-激酶（PI3-K）途径是一种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的GRP-R表达。根据我们的发现，该提案的中心假设是GRP通过GRP-R的激活刺激神经母细胞瘤细胞的生长，而GRP-R又受PI3-K信号转导途径的调节。为此，我们计划了以下具体目的：1）进一步表征人类神经母细胞瘤中GRP-R及其配体GRP的表达，2）描绘了调节神经细胞中GRP-R表达的分子机制，3）以确定GRP/GRP-R途径对神经细胞瘤生长的影响。了解调节GRP/GRP-R表达的因素将提供有关GRP作为神经母细胞瘤的自分泌生长因子的潜在死记硬背的新颖和重要信息。该信息具有临床意义，因为GRP-R或GRP的表达都可以作为预测肿瘤侵袭性或潜在对治疗的潜在反应的肿瘤标志物。此外，对调节神经母细胞瘤细胞生长的细胞机制和信号通路的更好理解可能会导致新型治疗水溶液作为这种毁灭性疾病的辅助治疗。