Autophagy in Pancreatic Neuroendocrine Tumor Growth and Metastasis

描述（由申请人提供）：自噬是一种细胞分解代谢过程，由独特的细胞膜内运输过程介导，并通过溶酶体降解活性执行。它在所有真核细胞中都是保守的，对各种生理事件至关重要。解除自噬的管制已被认为是多种人类疾病（包括癌症）的致病因素。最近的研究进展已经确定了自噬的核心分子途径，使我们有可能了解自噬在癌症进展中的作用机制，并开发出具有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，转移性胰腺神经内分泌肿瘤仍然无法治愈。因此，更好地了解胰腺神经内分泌肿瘤的分子进展和开发新的治疗药物来对抗这种毁灭性疾病是很重要的。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。然而，缺乏关于自噬在胰腺神经内分泌癌中的作用的体内研究。本研究通过禽病毒RCASBP和SV40大T抗原在胰腺神经内分泌肿瘤小鼠体内模型，探讨自噬在胰腺神经内分泌肿瘤生长和转移中的潜在作用。在此之前，我们通过该小鼠模型发现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，在本研究中，我们能够检测自噬对Bcl-xL和RHAMMB两种特定分子驱动的胰腺神经内分泌肿瘤转移的影响。本研究的成功将确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提供潜在的治疗价值。

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.