Role of Gastrin-releasing Peptide in Neuroblastoma

超出所提供的空间。神经母细胞瘤是婴儿和儿童最常见的颅外实体瘤，占儿童癌症相关死亡的15%以上。尽管最近在综合治疗方面取得了进展，但所有阶段肿瘤的总死亡率仍高达50%。作为一种神经内分泌肿瘤，神经母细胞瘤可产生多种胃肠激素，并且肽表达量与临床肿瘤行为相关，提示肠肽作为自分泌生长因子的潜在作用。胃泌素释放肽（GRP）是刺激正常组织和肿瘤组织生长的肠/神经肽，并且还被发现是某些癌症的自分泌生长因子。我们的研究已经确定了更积极的未分化的神经母细胞瘤中的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，提示GRP作为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（PI 3-K）途径，一个重要的信号转导途径参与细胞存活，调节神经母细胞瘤GRP-R的表达。基于我们的研究结果，这一建议的中心假设是，GRP刺激神经母细胞瘤细胞的生长，通过激活GRP-R，这反过来是由PI 3-K信号转导通路调节。为了验证这一点，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）描述神经母细胞瘤中调控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GRP/GRP-R表达的调控因子将为GRP作为神经母细胞瘤自分泌生长因子的潜在机制提供新的重要信息。该信息具有临床意义，因为GRP-R或GRP的表达可作为肿瘤标志物来预测肿瘤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的治疗剂作为这种毁灭性疾病的辅助治疗。性能现场=

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================