2016-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/707629摘要：胰臟癌是存活率最低的癌症。由於發生率逐年增加，預估胰臟癌在2020 年將成為美國第二大癌症死因。85％的胰臟癌發現時已達末期，因此急需能早期偵測胰臟癌的方法。40％的胰臟癌患者因癌細胞分泌未知的致糖尿病因子引發新生糖尿病(pancreatic cancer associated new-onset diabetes)，是早期發現的線索。本計劃希望找出胰臟癌之致糖尿病因子及闡明其誘發糖尿病之機轉，並由致糖尿病因子中篩選出能及早偵測胰臟癌的生物標記。我們已利用蛋白質體學(proteomics)由胰臟癌細胞株分泌之蛋白中鑑定出一些可能的致糖尿病因子。本計劃將進一步進行四項相關後續研究: (1) 找出胰臟癌細胞株分泌蛋白中所有可能的致糖尿病因子，檢視這些因子在胰臟癌組織是否表現及其對胰島素之分泌與感受性的影響，以確認胰臟癌分泌的致糖尿病因子。(2)闡明致糖尿病因子誘發糖尿病之機轉及訊息傳遞路徑。(3)比較胰臟癌與非胰臟癌(慢性胰臟炎、糖尿病、健康人)血液中致糖尿病因子的濃度以找出能早期偵測胰臟癌的生物標記組合，並分析生物標記與腫瘤分期、患者存活率之關連。(4) 建立胰臟癌新生糖尿病的動物模式。如何早期偵測胰臟癌是癌症領域的熱門課題。找出能早期診斷的生物標記可降低胰臟癌死亡率，闡明胰臟癌誘發糖尿病之機轉可對其發生與治療策略提供新看法。<br> Abstract: Pancreatic cancer (PC) is the most lethal cancer. Due to its increasing incidence, PC is projected tobecome the second leading cause of cancer deaths in USA by 2020. Surgical resection of tumor is the onlypotential cure, but early PC rarely causes symptoms and 85 % of patients present with terminal disease atdiagnosis, underscoring an urgent need for methods that enable early detection. A potential opportunity todetect PC 18 to 24 months before onset of symptoms is PC associated new-onset diabetes, which occurs inapproximately 40% of PC patients. Mounting evidence indicates that PC-associated new-onset diabetesresults from unknown tumor-secreted diabetogenic factors. This study aims to uncover these diabetogenicfactors and the molecular mechanisms underlying PC-associated new-onset diabetes, and to identifybiomarkers that enable early detection of PC from these diabetogenic factors.Using proteomics approaches, we have identified a list of PC-secreted proteins that have diabetogenicfunctions and are thus potential diabetogenic factors. To further build on these results, this 3-year projectproposes four interrelated studies: (1) pinpoint PC-produced diabetogenic factors: verify all potentialdiabetogenic factors from the secretome of PC cell lines, confirm their expression in human PC tissue, andassess their effects on insulin secretion and insulin sensitivity; (2) elucidate how diabetogenic factors affectsignaling pathways involved in insulin secretion and insulin sensitivity to induce diabetes; (3) develop andvalidate biomarkers that enable early detection of PC: compare blood levels of diabetogenic factors amongPC and non-PC subjects (chronic pancreatitis, diabetics, and healthy controls) to identify the bestcombination of biomarkers, validate its diagnostic performance in terms of the sensitivity, specificity, andaccuracy for differentiating PC from non-PC in a separate validation cohort, and assess the relation betweenthese biomarkers and tumor stage or patient survival; (4) establish an animal model of PC-associatednew-onset diabetes.Search for novel diagnostic biomarkers for PC is one of the hottest topics in cancer research. If ouraims are achieved, novel biomarkers that enable early detection may improve the grave prognosis of PC;elucidation of diabetogenic factors and mechanisms underlying PC-associated new-onset diabetes mayprovide novel insights into the pathogenesis of PC and yield novel therapeutic targets.胰臟癌胰臟癌之新發生糖尿病致糖尿病因子生物標記pancreatic cancerpancreatic cancer associated new-onset diabetesdiabetogenic factorsbiomarker