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

• 批准号: 8639507
• 负责人: Yi-Chieh Nancy Du
• 金额: $ 18.28万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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/8639507
• 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; Islet Cell Tumor; 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; 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

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并由溶酶体降解活性执行的细胞分解代谢过程。它在所有真核细胞中是保守的，对各种生理事件至关重要。自噬的失调已经被认为是多种人类疾病（包括癌症）的致病因素。最近的进展导致了自噬的中心分子途径的鉴定，使得有可能理解自噬在癌症进展中的作用的机制，并开发用于潜在治疗目的的自噬靶向药物。 胰腺神经内分泌肿瘤是胰腺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病率持续上升。大多数胰腺神经内分泌肿瘤在诊断时已经转移，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进展的分子机制，并开发新的治疗药物来对抗这种毁灭性的疾病。最近的证据，主要是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。然而，缺乏体内研究来解决自噬在胰腺神经内分泌癌中的作用。在本研究中，我们将通过使用禽类病毒RCASBP和SV 40大T抗原为基础的胰腺神经内分泌癌体内小鼠模型，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Bcl-xL和RHAMB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，在本提案中，我们能够检查自噬对由两种特定分子Bcl-xL和RHAMMB驱动的胰腺神经内分泌肿瘤转移的影响。该研究的成功将建立自噬在胰腺神经内分泌癌生长和转移中的作用，并为自噬靶向预防肿瘤生长和转移的潜在治疗价值提供见解。

项目成果

Expression of the receptor for hyaluronic acid mediated motility (RHAMM) is associated with poor prognosis and metastasis in non-small cell lung carcinoma.

• DOI: 10.18632/oncotarget.9554
• 发表时间: 2016-06-28
• 期刊: Oncotarget
• 作者: Wang D;Narula N;Azzopardi S;Smith RS;Nasar A;Altorki NK;Mittal V;Somwar R;Stiles BM;Du YN
• 通讯作者: Du YN