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，由独特的细胞内膜运输过程介导，并由溶酶体降解活动执行。它在所有真核细胞中都是保守的，对各种生理事件都是至关重要的。自噬的解除管制已被认为是包括癌症在内的多种人类疾病的致病因素。最近的进展导致了对自噬的中心分子途径的识别，使得理解自噬在癌症进展中的作用的潜在机制成为可能，并为潜在的治疗目的开发自噬靶向药物。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确诊时已经是转移性肿瘤，转移性胰腺神经内分泌肿瘤仍然无法治愈。因此，更好地从分子水平了解胰腺神经内分泌肿瘤的进展，并开发新的治疗药物来对抗这种毁灭性的疾病是很重要的。最近的证据，主要基于体外细胞培养和异种移植研究，表明自噬可能参与了胰腺肿瘤的发展。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，我们将利用禽类病毒RCASBP和SV40大T抗原建立胰腺神经内分泌癌的体内模型，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。此前，通过使用该小鼠模型，我们发现BclXL和RHAMMB的过表达可以刺激原发胰腺神经内分泌肿瘤的转移。因此，在这个方案中，我们能够检测自噬在两个特定分子：bclxl和rHAMMB驱动的胰腺神经内分泌肿瘤转移中的作用。这项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的潜在治疗价值提供见解。

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.