Role of Gastrin-releasing Peptide in Neuroblastoma

神经母细胞瘤是婴儿和儿童最常见的颅外实体瘤， 超过15%的儿童癌症相关死亡。尽管最近在综合治疗方面取得了进展- 然而，所有阶段的肿瘤的总死亡率仍然显著地为50%。作为神经内分泌 肿瘤，神经母细胞瘤可以产生各种胃肠（GI）激素和肽的量 表达与临床肿瘤行为相关，提示肠道肿瘤的潜在作用。 ）肽作为自分泌生长因子。胃泌素释放肽（GRP）是一种肠/神经肽，刺激- 促进正常组织和肿瘤组织的生长，也被发现是一种自分泌生长 一些癌症的因素。我们的研究已经确定了增加表达的GRP受体（GRP-R） 更有侵袭性的未分化神经母细胞瘤。此外，我们发现GRP在功能上 与GRP-R偶联刺激肿瘤生长，提示GRP作为自分泌生长因子的作用， 神经母细胞瘤此外，我们已经证明了磷脂酰肌醇3-激酶（PI 3-K）途径， 参与细胞存活的一个重要信号转导途径，调节GRP-R的表达， 神经母细胞瘤根据我们的研究结果，这个建议的中心假设是，GRP刺激 神经母细胞瘤细胞的生长通过GRP-R的激活，而GRP-R又由PI 3-K调节 信号转导途径为此，我们计划了以下具体目标：1）进一步 描述GRP-R及其配体GRP在人神经母细胞瘤中的表达，2）描述GRP-R及其配体GRP在人神经母细胞瘤中的表达， 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的因素 表达将提供新的和重要的信息，关于潜在的rote玻璃钢作为一个 神经母细胞瘤的自分泌生长因子该信息具有临床意义，因为 GRP-R或GRP的表达可作为预测肿瘤侵袭性或潜能的肿瘤标志物 对治疗的反应。此外，更好地理解细胞机制和信号传导 调节神经母细胞瘤细胞生长的途径可能会导致新的 作为辅助治疗这种毁灭性疾病的治疗剂。

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.