2019-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/706275摘要：胰臟癌即將成為美國第二大癌症死因，是存活率最低的癌症。胰臟癌發現時85％已達末期，治療效果不佳。80%病患因胰臟癌引發全身炎症導致惡病質(cachexia)，約30%病患死於惡病質引發之營養不良、肌肉流失與免疫缺陷。因此急需早期偵測胰臟癌的方法與針對胰臟癌及惡病質的有效治療。胰臟癌會分泌不明因子引發胰臟癌相關糖尿病(pancreatic cancer associated diabetes)，找出此因子有助早期發現胰臟癌。我們之前的研究發現S100A9及galectin-3是胰臟癌分泌的致糖尿病因子，此二因子在誘發糖尿病的腫瘤中過度表現，其血中濃度可區分胰臟癌相關糖尿病與第二型糖尿病，並且會抑制肌肉細胞攝取葡萄糖與抑制胰島細胞分泌胰島素，然而其機轉不明。因其主要功能為促進發炎，我們假設此二因子也會誘發全身炎症與惡體質，為潛在之預後預測因子與治療標的。因此本計畫將進行四項研究：(1)確認S100A9及galectin-3是否經TLR4活化IKK-β而抑制肌肉細胞攝取葡萄糖; (2)闡明其抑制胰島素分泌之機轉; (3)前瞻性探索與驗證S100A9及galectin-3血中濃度對全身炎症/惡病質程度、治療效果及病患存活之預測力; (4)以動物模式驗證S100A9及galectin-3誘發糖尿病與惡病質之能力及抑制相關傳導路徑之療效。本計畫將闡明此二因子誘發糖尿病之機轉及其與惡病質之關聯，以及成為嶄新生物標記與治療標的之可能性。<br> Abstract: Pancreatic cancer (PC) is the most lethal cancer, and is projected to become the second leading cause of cancer deaths in USA by 2020. About 85 % of patients present with unresectable tumors at diagnosis, and current treatments have only modest survival benefit. Furthermore, approximately 80% of PC patients develop cachexia which manifests as systemic inflammation, refractory malnutrition, muscle loss, and immunodeficiency and accounts for death in 30% of patients. Therefore, there is an urgent need for methods to enable early detection and effective treatments for PC and cachexia to improve the grave prognosis. Approximately 50% of PC patients develop PC-associated diabetes mellitus (PCDM), a paraneoplastic phenomenon mediated by obscure tumor-secreted factors and characterized by marked insulin resistance. Identifying the diabetogenic factors may enable early detection of PC. We have found that S100A9 and galectin-3 are differentially overexpressed in tumors from patients with PCDM, and serum galectin-3 and S100A9 levels distinguish PCDM from type 2 diabetes in patients with new-onset diabetes. Furthermore, galectin-3 and S100A9 inhibit insulin-stimulated glucose uptake in muscle cells and suppress insulin secretion in beta cells. Collectively, our findings support that galectin-3 and S100A9 are novel PC-produced diabetogenic factors, but the underlying mechanisms remain unclear. Because S100A9 and galectin-3 have potent proinflammatory activities, we hypothesize that overexpression of galectin-3 and S100A9 in PC may also induce systemic inflammation/cachexia in PC and negatively impacts patient outcomes. Therefore, this 3-year project proposes four interrelated studies: (1) verify our preliminary findings suggesting that galectin-3 and S100A9 suppress glucose uptake in muscle cells through toll like receptor 4 (TLR4) and downstream IKK-β activation; (2) elucidate the mechanisms by which galectin-3 and S100A9 suppress insulin secretion in beta cells; (3) prospectively evaluate the relation between serum galectin-3 and S100A9 levels and severity of systemic inflammation/cachexia, treatment response, and survival in PC patients and validate their usefulness as predictive biomarkers; (4) verify the diabetogenic and procachetic effects of galectin-3 and S100A9 and explore the potential therapeutic benefits of targeting related signaling pathways in PC xenograft models.This project is expected to uncover the cognate receptors of S100A9 and galectin-3 and downstream signaling pathways that suppress glucose uptake and insulin secretion, reveal the usefulness of S100A9 and galectin-3 as indices of cachexia and predictors of treatment response and survival in patients, and explore their potential as novel therapeutic targets for PC. The results may provide new insights and biomarkers for PC and cachexia and yield novel therapeutic strategies.胰臟癌相關糖尿病惡病質S100A9galectin-3生物標記pancreatic cancer associated diabetescachexiaS100A9galectin-3biomarker.