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: 7749604
• 负责人: DAI H. CHUNG
• 金额: $ 5.2万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749604
• 关键词: 1-Phosphatidylinositol 3-Kinase; 5 year old; Accounting; Adjuvant; Affect; Award; Behavior; Bombesin; Bombesin Receptor; Breast; Cell Surface Receptors; Cell physiology; Cells; 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; gastrointestinal; high risk; hormone regulation; in vivo; innovation; lung small cell carcinoma; mortality; mouse model; neoplastic; new therapeutic target; novel; novel therapeutics; outcome forecast; overexpression; paracrine; public health relevance; receptor; receptor coupling; receptor expression; research study; response; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): 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 Neuroblastoma 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 Neuroblastoma., 2) to discern the exact role of PI3K/Akt pathway during GRP/GRPR-mediated cell signaling in human Neuroblastoma, 3) to ascertain the effects of targeting GRP/GRPR expression on in vivo tumor growth and metastatic potential of Neuroblastoma. 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 Neuroblastoma s. Furthermore, these studies will also enhance our knowledge of hormone- regulated cancer pathogenesis by elucidation of the complex signaling pathways involved. PUBLIC HEALTH RELEVANCE: In spite of advances in therapy, patients with Neuroblastoma still have a staggering mortality rate of 50%. This highly malignant childhood tumor is derived from cells of neural crest origin and as such, its tumor behavior is significantly affected by neuroendocrine peptides. Our project is clinically significant because it will aid in the understanding of the hormonal regulation of Neuroblastoma, which could lead to a breakthrough in the treatment of this devastating disease.

描述（由申请人提供）：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。尽管最近在联合治疗方面取得了进展，但所有阶段肿瘤的总体死亡率仍然高达 50%。作为一种神经嵴源性肿瘤，神经母细胞瘤可以产生多种胃肠道（GI）激素，从而影响肿瘤进展。我们已经确定胃泌素释放肽（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发挥作用，充当自分泌/旁分泌生长因子。我们还发现，GRPR 表达在体外调节神经母细胞瘤细胞的贴壁独立性，并且 GRPR 刺激在体内增加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 敲低可有效阻止肿瘤的发展和转移。此外，我们的研究还发现磷脂酰肌醇 3 激酶 (PI3K) 通路是 GRPR 介导的肿瘤进展的一种新兴信号机制。此外，PI3K 通路成分受 GRPR 过度表达和沉默的调节。根据我们的初步研究结果，该提案的中心假设是 GRP/GRPR 表达通过激活关键的 PI3K 信号转导途径来关键调节神经母细胞瘤的肿瘤发生。为了检验这一假设，我们计划了以下具体目标的实验：1) 确定 GRP/GRPR 机制对人类神经母细胞瘤重要致瘤过程的细胞功能。2) 辨别 PI3K/Akt 通路在 GRP 过程中的确切作用/GRPR 介导的人神经母细胞瘤中的细胞信号传导，3) 以确定靶向 GRP/GRPR 表达对体内肿瘤生长和神经母细胞瘤转移潜力的影响。更好地了解调节神经母细胞瘤肿瘤发生的细胞机制和信号通路可能会导致开发新型治疗剂作为这种破坏性疾病的辅助治疗。该信息具有临床意义，因为 GRPR 可能是高危神经母细胞瘤的重要新型治疗靶点。此外，这些研究还将通过阐明所涉及的复杂信号通路来增强我们对激素调节的癌症发病机制的了解。公共卫生相关性：尽管治疗取得了进步，神经母细胞瘤患者的死亡率仍然高达 50%。这种高度恶性的儿童肿瘤源自神经嵴起源的细胞，因此，其肿瘤行为显着受到神经内分泌肽的影响。我们的项目具有临床意义，因为它将有助于了解神经母细胞瘤的激素调节，这可能会导致这种破坏性疾病的治疗取得突破。