Mechanisms of Gastrin-Releasing Peptide-Mediated Neuroblastoma Growth

描述（申请人提供）：本人主要研究方向为g蛋白偶联受体（GPCR）信号通路在儿童颅外实体瘤细胞增殖过程中的作用机制。神经母细胞瘤是婴幼儿最常见的颅内外实体瘤。尽管目前在治疗方面取得了进展，但肿瘤各阶段的总死亡率仍保持在50%。神经母细胞瘤是一种神经内分泌肿瘤，可分泌多种胃肠道多肽并对其产生反应。我们和其他人之前已经表明，胃泌素释放肽（GRP）通过与GPCR结合，作为神经母细胞瘤细胞的自分泌/旁分泌生长因子。我们还发现更具侵袭性、未分化的神经母细胞瘤表达增加的GRP受体（GRPR）蛋白。磷脂酰肌醇3-激酶（PI3K）是一个关键的细胞存活途径，最近被证明是多种癌症的重要信号机制。我们报道了在未分化的神经母细胞瘤中，PI3K的负调节因子PTEN的表达降低。我们的研究也表明GRP激活了这一途径。根据我们的初步发现，本提案的中心假设是GRP可以通过激活PI3K通路调节神经母细胞瘤的生长。为了验证我们的假设，我们计划了以下具体目标：1)进一步确定GRP/GRPR信号通路对神经母细胞瘤细胞生长的下游表型效应；2)确定GRP诱导PI3K活化的分子调控机制。更好地了解grp诱导的神经母细胞瘤细胞增殖的细胞机制和信号通路，可能会导致开发新的药物来加强这种近乎致命的疾病的治疗。神经母细胞瘤是一种常见的儿童肿瘤，起源于神经嵴细胞；它通常发生在三岁以下儿童的肾上腺。尽管在治疗选择方面取得了进展，神经母细胞瘤患者的死亡率仍然高达50%。这项研究具有重要的临床意义，因为它将提高我们对这种儿童癌症的认识，并可能为这种毁灭性肿瘤的治疗提供突破。

DESCRIPTION (provided by applicant): My research interests center on the study of the G-protein coupled receptor (GPCR) signaling mechanisms involved in the pathogenesis of pediatric extracranial solid tumor cell proliferation. Neuroblastoma is the most common pediatric extracranial solid tumor in infants and children. Despite current advances in therapy, the overall mortality for all stages of the tumor remains at 50%. As a neuroendocrine tumor, neuroblastoma secretes and responds to various gastrointestinal peptides. We and others have previously shown that gastrin-releasing peptide (GRP), by binding to a GPCR, acts as an autocrine/paracrine growth factor for neuroblastoma cells. We also identified that more aggressive, undifferentiated neuroblastomas express increased GRP receptor (GRPR) protein. The phosphatidylinositol 3-kinase (PI3K) is a key cell survival pathway that has recently been demonstrated to be an important signaling mechanism in various cancers. We have reported decreased expression of PTEN, the negative regulator of PI3K, in undifferentiated neuroblastomas. Our studies have also revealed that GRP activates this pathway. Based on our preliminary findings, the central hypothesis of this proposal is that GRP can regulate the growth of neuroblastoma through PI3K pathway activation. To investigate our hypothesis, we have planned the following Specific Aims: 1) to further determine the downstream phenotypic effects of the GRP/GRPR signaling pathway on neuroblastoma cell growth, and 2) to identify the molecular mechanisms regulating GRP-induced PI3K activation. A better understanding of the cellular mechanisms and signaling pathways involved in GRP-induced neuroblastoma cell proliferation could result in the development of novel agents to enhance treatment of this near-fatal disease. Relevance Neuroblastoma is a common childhood cancer derived from cells of neural crest origin; it usually occurs in the adrenal gland in children under three years old. In spite of the advances in treatment options, patients with neuroblastoma still have a staggering mortality rate of 50%. This research is clinically significant because it will enhance our knowledge on this childhood cancer and could provide a breakthrough in the treatment of this devastating tumor.