Autophagy in Pancreatic Neuroendocrine Tumor Growth and Metastasis

自噬在胰腺神经内分泌肿瘤生长和转移中的作用

基本信息

批准号：
8512037
负责人：
Yi-Chieh Nancy Du
金额：
$ 24.25万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8512037
关键词：
Address Affect Animals Autophagocytosis Birds Cancer cell line Carcinoma Catabolic Process Cell Culture Techniques Cells Development Diagnosis Disease Engineering Eukaryotic Cell Event Genes Genetic Goals Growth In Vitro Incidence Infection Intracellular Membranes Islet Cell Islets of Langerhans Knowledge Large T Antigen Lead Lesion Malignant Neoplasms Malignant neoplasm of pancreas Mediating Membrane Protein Traffic Metastatic Neoplasm to the Liver Modeling Molecular Monitor Mus Mutation Neoplasm Metastasis Neuroendocrine Tumors Neurosecretory Systems Nude Mice Pancreas Pancreatic Ductal Carcinoma Pathogenesis Pathway interactions Patients Physiological Play Premalignant Primary Neoplasm Process Property RNA Interference Research Role SV40 T Antigens Simian virus 40 Stress Subcutaneous Injections System Therapeutic Therapeutic Agents Time Viral Tumor Antigens Virus Xenograft procedure base biological adaptation to stress cancer cell combat human disease in vivo inhibition of autophagy insight lymph nodes mouse model neoplastic cell novel strategies novel therapeutic intervention novel therapeutics overexpression pancreatic neoplasm prevent promoter public health relevance receptor response small hairpin RNA success tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Autophagy is a cellular catabolic process mediated by a unique intracellular membrane trafficking process and executed by lysosomal degrading activity. It is conserved in all eukaryotic cells and crucial for various physiological events. Deregulation of autophagy has been implicated as a pathogenic factor for multiple human diseases, including cancer. Recent progresses have led to the identification of a central molecular pathway for autophagy, making it possible to understand the mechanism underlying the role of autophagy in cancer progression and to develop autophagy-targeted agents for potential therapeutic purposes. Pancreatic neuroendocrine tumors are the second most common malignancy of the pancreas. The incidence of pancreatic neuroendocrine tumors has continued to rise in recent decades. Most pancreatic neuroendocrine tumors are already metastatic by the time they are diagnosed, and metastatic pancreatic neuroendocrine tumors remain incurable. It is therefore important to get better molecular understanding of pancreatic neuroendocrine tumors progression and to develop new therapeutic agents for combating this devastating disease. Recent evidence, largely based on in vitro cell culture and xenograft studies, suggests that autophagy might be involved in pancreatic tumor development. However, there lacks in vivo studies to address the role of autophagy in pancreatic neuroendocrine cancer. In this proposal, by using an avian virus RCASBP and SV40 large T antigen-based in vivo mouse model for pancreatic neuroendocrine cancer, we will investigate the potential role of autophagy in pancreatic neuroendocrine tumor growth and metastasis. Previously, by using this mouse model, we uncovered that overexpression of Bcl-xL and RHAMMB can stimulate metastasis of primary pancreatic neuroendocrine tumors. Therefore, in this proposal we are able to examine the effect of autophagy on pancreatic neuroendocrine tumor metastasis driven by the two specific molecules: Bcl-xL and RHAMMB. Success of the proposed research will establish the role of autophagy in growth and metastasis of pancreatic neuroendocrine cancer, and provide insights into the potential therapeutic value of autophagy-targeting in preventing outgrowth and metastasis of tumors.

描述（由申请人提供）：自噬是由独特的细胞内膜运输过程介导的细胞分解代谢过程，并由溶酶体降解活性执行。它在所有真核细胞中都是保守的，对于各种生理事件至关重要。自噬的放松管制已被视为包括癌症在内的多种人类疾病的致病因素。最近的进展导致了自噬的中央分子途径的鉴定，从而有可能了解自噬在癌症进展中作用的机制，并开发出靶向自噬剂以实现潜在治疗目的。胰腺神经内分泌肿瘤是胰腺中第二常见的恶性肿瘤。近几十年来，胰腺神经内分泌肿瘤的发生率一直在升高。大多数胰腺神经内分泌肿瘤在被诊断时已经是转移性的，并且转移性胰腺神经内分泌肿瘤仍然无法治愈。因此，重要的是要更好地了解胰腺神经内分泌肿瘤的进展，并开发新的治疗剂来打击这种毁灭性疾病。最近的证据主要基于体外细胞培养和异种移植研究，表明自噬可能参与胰腺肿瘤的发展。但是，缺乏体内研究来解决自噬在胰腺神经内分泌癌中的作用。在该提案中，通过使用禽病毒RCASBP和SV40基于T抗原小鼠模型的胰腺神经内分泌癌，我们将研究自噬在胰腺神经内分泌肿瘤生长和转移中的潜在作用。以前，通过使用这种小鼠模型，我们发现了Bcl-XL和RHAMMB的过表达可以刺激原发性胰腺神经内分泌肿瘤的转移。因此，在此提案中，我们能够检查自噬对由两个特定分子驱动的胰腺神经内分泌肿瘤转移的影响：Bcl-XL和RHAMMB。拟议的研究的成功将确定自噬在胰腺神经内分泌癌的生长和转移中的作用，并提供对自噬靶向的潜在治疗价值在预防肿瘤的生长和转移中的潜在治疗价值。