Surgical Studies on the Role on Gastrin-releasing Peptide in Neuroblastoma

摘要 神经母细胞瘤是儿科人群中最常见的颅外实体瘤， 占婴儿和儿童所有癌症相关死亡的15%以上。尽管 综合治疗的最新进展，所有阶段肿瘤的总死亡率 仍然显著高于50%。作为一种神经嵴源性肿瘤，神经母细胞瘤可以产生 各种胃肠道（GI）激素，可影响肿瘤进展。我们有 确定胃泌素释放肽（GRP）及其受体（GRPR）的表达， 在侵袭性、未分化的神经母细胞瘤和GRP中增加，通过GRPR起作用， 作为自分泌/旁分泌生长因子。我们还发现GRPR表达 调节体外神经母细胞瘤细胞的锚定独立性， 增加体内神经母细胞瘤异种移植物的生长和血管生成。而且我们 在体内沉默技术方面取得了令人兴奋的创新进展，我们发现， GRPR敲低有效地阻断了肿瘤的发展和转移。此外，我们的 研究已经确定磷脂酰肌醇3-激酶（PI 3 K）途径是一种紧急的 GRPR介导的肿瘤进展的信号传导机制。此外，PI 3 K通路 GRPR基因的表达和沉默是调控基因表达的重要因素。根据我们初步的 研究结果表明，该提议的中心假设是GRP/GRPR表达至关重要 通过激活关键的PI 3 K信号调节神经母细胞瘤肿瘤发生 转导途径为了验证这一假设，我们计划用 以下具体目的：1）确定GRP/GRPR机制的细胞功能， 在人类神经母细胞瘤的基本致瘤过程，2）辨别的确切作用 人神经母细胞瘤中GRP/GRPR介导的细胞信号传导过程中的PI 3 K/Akt通路，3） 确定靶向GRP/GRPR表达对体内肿瘤生长和转移的影响 神经母细胞瘤的潜力。更好地理解细胞机制和信号传导 调节神经母细胞瘤肿瘤发生的途径可能会导致 作为这种毁灭性疾病的辅助治疗的新型治疗剂。该信息 临床意义，因为GRPR可能是一个重要的新的治疗靶点，高风险 神经母细胞瘤此外，这些研究还将提高我们对激素的认识- 通过阐明所涉及的复杂信号通路来调节癌症发病机制。

ABSTRACT Neuroblastoma is the most common extracranial solid tumor in the pediatric population, accounting for greater than 15% of all cancer-related deaths in infants and children. Despite recent advances in combined modality treatment, the overall mortality for all stages of tumors remains significant at 50%. As a neural crest-derived tumor, neuroblastoma can produce various gastrointestinal (GI) hormones which can affect tumor progression. We have determined that expressions of gastrin-releasing peptide (GRP) and its receptor (GRPR) are increased in aggressive, undifferentiated neuroblastomas and that GRP, acting through GRPR, acts as an autocrine/paracrine growth factor. We have also found that GRPR expression regulates anchorage-independence in neuroblastoma cells in vitro and that GRPR stimulation increases the growth and angiogenesis of neuroblastoma xenografts in vivo. Moreover, we have made exciting innovative progress with in vivo silencing techniques, where we found that GRPR knockdown effectively blocked tumor development and metastasis. Additionally, our studies have identified the phosphatidylinositol 3-kinase (PI3K) pathway as an emergent signaling mechanism for GRPR-mediated tumor progression. Furthermore, PI3K pathway components are regulated by GRPR overexpression and silencing. Based on our preliminary findings, the central hypothesis of this proposal is that GRP/GRPR expression critically regulates neuroblastoma tumorigenesis through the activation of the crucial PI3K signal transduction pathway. To examine this hypothesis, we have planned experiments with the following Specific Aims: 1) to determine the cellular function of GRP/GRPR mechanisms on essential tumorigenic processes in human neuroblastomas, 2) to discern the exact role of PI3K/Akt pathway during GRP/GRPR-mediated cell signaling in human neuroblastomas, 3) to ascertain the effects of targeting GRP/GRPR expression on in vivo tumor growth and metastatic potential of neuroblastomas. A better understanding of the cellular mechanisms and signaling pathways regulating neuroblastoma tumorigenesis could potentially lead to the development of novel therapeutic agents as adjuvant treatment for this devastating disease. This information is clinically significant because GRPR may be an important novel therapeutic target for high-risk neuroblastomas. Furthermore, these studies will also enhance our knowledge of hormone- regulated cancer pathogenesis by elucidation of the complex signaling pathways involved.