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

胃泌素释放肽在神经母细胞瘤中作用的外科研究

• 批准号: 8288195
• 负责人: DAI H. CHUNG
• 金额: $ 33.26万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288195
• 关键词: 1-Phosphatidylinositol 3-Kinase; 5 year old; Accounting; Adjuvant; Affect; Award; Behavior; Bombesin; Bombesin Receptor; Breast; Cell Surface Receptors; Cell physiology; Cephalic; Cessation of life; Characteristics; Child; Childhood; Colon Carcinoma; Combined Modality Therapy; Complex; Development; Diagnostic Neoplasm Staging; Disease; Endocrine; Funding; GRP gene; Gastrin releasing peptide; Gastrointestinal Hormones; Gastrointestinal tract structure; Goals; Growth; Growth Factor; Hormone Responsive; Hormones; Human; In Vitro; Infant; Interleukin-2; Knowledge; Lead; Life; Ligands; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Methods; Modality; Mucous Membrane; Neoplasm Metastasis; Neural Crest; Neural Crest Cell; Neuroblastoma; Neuropeptides; Neurosecretory Systems; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Peptides; Population; Process; Progress Reports; Property; Prostate; RNA Interference; Refractory; Relapse; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Solid Neoplasm; Staging; Techniques; Therapeutic; Therapeutic Agents; Tissues; Tumor Biology; Tumor stage; Tumor-Derived; Undifferentiated; Xenograft procedure; angiogenesis; autocrine; base; cell growth; clinically significant; high risk; hormone regulation; in vivo; innovation; lung small cell carcinoma; mortality; mouse model; neoplastic; neuroblastoma cell; new therapeutic target; novel; novel therapeutics; outcome forecast; overexpression; paracrine; receptor; receptor coupling; receptor expression; research study; response; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

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.

抽象的 神经母细胞瘤是儿科人群中最常见的颅外实体瘤， 占所有婴儿和儿童癌症相关死亡的 15% 以上。尽管 联合治疗的最新进展，所有阶段肿瘤的总体死亡率 仍然显着在 50%。作为一种神经嵴源性肿瘤，神经母细胞瘤可以产生 各种可以影响肿瘤进展的胃肠道（GI）激素。我们有 确定胃泌素释放肽（GRP）及其受体（GRPR）的表达 在侵袭性、未分化神经母细胞瘤中增加，并且 GRP 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 体外调节神经母细胞瘤细胞的贴壁独立性，GRPR 刺激 增加体内神经母细胞瘤异种移植物的生长和血管生成。此外，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敲低有效阻止肿瘤的发展和转移。此外，我们的 研究已确定磷脂酰肌醇 3 激酶 (PI3K) 途径是一种新兴的途径 GRPR 介导的肿瘤进展的信号机制。此外，PI3K通路 组分受 GRPR 过度表达和沉默的调节。根据我们的初步 研究结果表明，该提案的中心假设是 GRP/GRPR 表达关键 通过激活关键的 PI3K 信号来调节神经母细胞瘤的肿瘤发生 转导途径。为了验证这一假设，我们计划进行实验 具体目标如下： 1) 确定 GRP/GRPR 机制的细胞功能 人类神经母细胞瘤的重要致瘤过程，2）辨别其确切作用 人神经母细胞瘤中 GRP/GRPR 介导的细胞信号转导过程中的 PI3K/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。更好地了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 新型治疗剂作为这种破坏性疾病的辅助治疗。该信息是 具有临床意义，因为 GRPR 可能是高危患者的一个重要的新型治疗靶点 神经母细胞瘤。此外，这些研究还将增强我们对激素的了解 通过阐明所涉及的复杂信号通路来调节癌症发病机制。