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

描述(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，占所有婴儿和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脊源性肿瘤，可产生多种胃肠激素，影响肿瘤的进展。我们已确定胃泌素释放肽(GRP)及其受体(GRPR)在侵袭性未分化神经母细胞瘤中的表达增加，GRP通过GRPR发挥自分泌/旁分泌生长因子的作用。我们还发现，在体外，GRPR的表达调节神经母细胞瘤细胞的锚定独立性，在体内，GRPR的刺激增加了神经母细胞瘤异种移植瘤的生长和血管生成。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基因敲除有效地阻止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(PI3K)通路是GRPR介导的肿瘤进展的紧急信号机制。此外，PI3K通路元件受GRPR过表达和沉默的调节。根据我们的初步发现，这一建议的中心假设是GRP/GRPR的表达通过激活关键的PI3K信号转导通路而关键地调节神经母细胞瘤的发生。为了验证这一假设，我们计划进行以下实验：1)确定GRP/GRPR机制在人神经母细胞瘤发生过程中的细胞功能；2)明确PI3K/Akt通路在人神经母细胞瘤GRP/GRPR介导的细胞信号转导中的确切作用；3)确定靶向GRP/GRPR表达对神经母细胞瘤体内肿瘤生长和转移潜能的影响。更好地了解调控神经母细胞瘤发生的细胞机制和信号通路可能会导致开发新的治疗剂作为这种毁灭性疾病的辅助治疗。这一信息具有重要的临床意义，因为GRPR可能是高危神经母细胞瘤S的一个重要的新的治疗靶点。此外，这些研究还将通过阐明涉及的复杂信号通路来增强我们对激素调节癌症发病机制的认识。公共卫生相关性：尽管在治疗方面取得了进步，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来源于神经脊来源的细胞，因此，其肿瘤行为受到神经内分泌肽的显著影响。我们的项目具有重要的临床意义，因为它将有助于了解神经母细胞瘤的激素调节，这可能导致在这种毁灭性疾病的治疗方面取得突破。

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.