Role of Gastrin-releasing Peptide in Neuroblastoma

超出提供的空间。神经母细胞瘤是婴幼儿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%。神经母细胞瘤是一种神经内分泌肿瘤，可产生多种胃肠道(GI)激素，其多肽的表达与临床肿瘤行为密切相关，提示肠道多肽作为自分泌生长因子具有潜在的作用。胃泌素释放肽(GRP)是一种促进正常组织和肿瘤组织生长的肠道/神经肽，也被发现是某些癌症的自分泌生长因子。我们的研究发现，在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，提示GRP作为神经母细胞瘤的自分泌生长因子的作用。此外，我们还证明了磷脂酰肌醇3-激酶(PI3-K)途径是参与细胞存活的重要信号转导途径，它调节神经母细胞瘤中GRP-R的表达。根据我们的发现，这一建议的中心假设是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PI3-K信号转导通路的调节。为了进一步研究神经母细胞瘤中GRP-R及其配体GRP的表达，探讨神经母细胞瘤中GRP-R表达的分子机制，确定GRP/GRP-R通路在神经母细胞瘤生长中的作用。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作用提供新的和重要的信息。这一信息具有临床意义，因为GRP-R或GRP的表达可作为预测肿瘤侵袭性或潜在治疗反应的肿瘤标志物。此外，更好地了解调控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药物作为这种毁灭性疾病的辅助治疗。表演网站========================================Section End===========================================

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===========================================