2015-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644426摘要：沒有功能性的胰臟神經內分泌細胞瘤，因為生長速度慢而沒有症狀，等到診 斷出來時，約46%—93%已經有肝臟轉移。而這些肝臟轉移的有無及範圍卻是 影響病人存活的最重要因子之一。卻鮮有胰臟神經內分泌細胞瘤肝轉移機制的 研究。有許多文獻報告腫瘤轉移的形成除了種子與土壤之外肥料也非常重要，肥料 由原發腫瘤分泌後隨著血流運送至土壤而形成一些適合種子生長的環境〔pre-metastatic niche)。而大部分的肥料都是以外分泌體〔exosomes〕的型態打包及運送，這樣可以避免肥料在運送過程中被分解或稀釋掉。相對於胰外分泌細胞癌，胰臟神經內分泌細胞瘤的生長速度是很慢的〔大都是 G1,Ki 67 index ^ 2〕。生長速度這麼慢卻有這麼高的比率會形成肝臟轉移的原因 很可能是胰臟神經內分泌細胞瘤會分泌特殊的外分泌體影響了肝臟這片土壤讓 生長速度雖然慢的種子卻能存活並成長至轉移病灶。本計畫預備利用我們實驗 室已有的外分泌體分離、定量及染色的技術，及把戴有螢光的腫瘤細胞注射入 脾臟讓其循環至肝臟而形成腫瘤的動物實驗模式來測試外分泌體在胰臟神經內 分泌細胞瘤肝轉移的過程中所扮演的角色，再進一步研究是肝臟中的哪一種細 胞會攝取外分泌體，攝取之後會有何特殊基因表現而釋放出特定的物質去影響 周圍的土壤、土壤所發生的具體變化，及用質譜儀分析外分泌體的蛋白質成分， 以尋找外分泌體中真正能影響土壤的成分，再藉由拮抗這些成分測試是否能阻 斷肝轉移的形成。當然最後也會測試胰臟神經內分泌細胞瘤的病人的外分泌體 中該成分的濃度是否與肝臟轉移的存在與否是否有相關性。我們深信這個計畫 的研究成果將有助於了解胰臟神經內分泌細胞瘤肝臟轉移的機制，也將有助於 其診斷及治療。<br> Abstract: Hepatic metastases develop in roughly 46% to 93% of patients with nonfunctioningneuroendocrine tumors (NETs) at time of diagnosis because of tumor’s indolentnature. Although hepatic metastasis is one of the most important factors for survivalof patients with pancreatic NETs, its mechanism has seldom been studied.It has been well known that both seeds and soil are important for the formation ofneoplasm metastasis. Recently, more and more papers reported that pre-metastaticniches induced by tumor-secreted exosomes are the third important metastatic factor.Compared to pancreatic ductal cell adenocarcinoma cells, most pancreatic NETs cellshave much slower growth rate reflected by low Ki 67 index (􀃙 2). In spite of theindolent nature, hepatic metastases develop in roughly 46% to 93% of patients withnonfunctioning neuroendocrine tumors (NETs) at time of diagnosis. Therefore, wepostulate that exosomes-induced pre-metastatic niche will be extraordinary importantfor the growth of the metastatic pancreatic NETs cells with indolent nature.The aim of this project is to study the role of exosomes in hepatic metastasis ofpancreatic NETs. We have successfully isolated and quantified exosomes fromculture medium of both murine NIT-1 and TGP61 and human BON and QGP-1 NETscell lines. We have also successfully fluorescently labeled the isolated exosomes withPKH67 membrane dye (Sigma). Animal model of hepatic metastases from pancreaticNETs has also been established by intra-splenic injection of murine TGP61 NETstumor cells. We will use all of these techniques to test whether exosomes secreted bypancreatic NETs play a role in the process of hepatic metastasis.胰臟神經內分泌瘤肝臟轉移外分泌體Pancreatic neuroendocrine tumorLiver metastasesexosome