2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644279摘要：超過90%的胰臟癌是管狀細胞癌，其特色為晚期發現，早期轉移1 及對傳統化療無效。2只有少數能手術切除，手術後許多也會復發，因此化療對胰臟癌的治療應該是非常重要的，可惜至目前為止其效果仍是不彰的。纖維化是胰臟管狀細胞癌的一大特色3,4，胰臟星狀細胞在胰臟管狀細胞癌的纖維化扮演最重要的角色5-7，胰臟星狀細胞也參與於胰臟癌的抗化療.10，因此研究胰臟癌的化療，應同時研究胰臟星狀細胞。在2009 的Science 期刊11 Oliver KP 報告了「在小鼠胰臟癌的模式藉由抑制胰臟星狀細胞hedgehog 訊息可提高胰臟癌腫瘤內血管密度及到達的藥物濃度繼而提高化療效果」。可惜其效果只是短暫的，不過也顯示出治療胰臟癌不只要治療胰臟癌細胞，也必須同時治療胰臟纖維化，才可能提升治療效果。在2009 的Hepatology 期刊也報告Rac1, TGF-β, PDGF 會促進胰臟星狀細胞的hedgehog 訊息.12 由於肝臟與胰臟星狀細胞是非常類似的(在21329 個基因表現上胰臟與肝臟星狀細胞只有29 個不同) 13，因此肝硬化的有效治療方式理論上將能用於治療胰臟纖維化，本計畫將嘗試使用「我們之前用Interferon-α治療肝硬化的經驗(Moleecular Therapy 200814)」及「之前實驗建立的小鼠纖維化胰臟癌模式(J Hepatology 2009)」研究「是否可用Interferon-α影響TGFβ1所提升hedgehog 主導的胰臟星狀細胞的活化，進而降低胰臟癌的抗化療性」。<br> Abstract: More than 90% of pancreatic cancers represent PDA, which are characterized by alate detection, a rapid progression, early systemic dissemination,1 late diagnosis and arelative resistance to conventional chemo- and radiotherapy.2A strong desmoplastic reaction is characteristics for PDA.3,4 Many reports haveprovided strong evidence that pancreatic stellate cells (PSCs) play a central role infibrogenesis associated with pancreatic ductal adenocarcinoma.5-7Our previous8 and Bachem’s9 studies showed that by producing TGFβ1 and PDGFother fibrogenic mediators, PCCs stimulate the transformation of the quiescent fat-storingphenotype of PSCs to the highly active myofibroblast-like phenotype. In addition, PCCsattract PSCs and stimulate motility, proliferation and matrix synthesis of PSCs. The result ofthis stimulation is a strong desmoplastic reaction surrounding carcinoma tissue. Manyauthors showed PSCs play a major role in tumor progression, metastasis, and drugresistance of pancreatic ductal cancer.10 Accumulating data indicate that PSC participate inthe development of chemoresistance in PDA. Accordingly, research focusing on theimprovement of anticancer drug efficiency should not exclusively study CC, but alwaysconsider the influence of stroma cells.A recent study reported major progress in respect to reduce chemotherapy resistance inPDA.11 Inhibition of hedgehog signaling (involved in tumor-stroma interaction) in a murinemodel of PDA reduced stroma expansion thereby increasing intratumorl vascular densityand intrtumor concentration of gemicitabine leading to transient stabilization of disease.11Rac1, TGF-β, PDGF were reported to promote hedgehog-mediated acquisition of themyofibroblastic phenotype in rat and human HSCs.12 A genom-wide assessment of geneexpression that included 21329 genes identified only 29 that were differentially expressedbetween cultures of primary HSCs and PSCs.13 Our previous study shows Interferon-αtreatment can ameliorates liver cirrhosis by reducing TGF-β expression.14 The fact that theoverwhelming majority of genes show no differences in expression supports the notion thatHSCs and PSCs are very similar. Therefore, we presume that treatments effective for livercirrhosis will also be useful for treatment of pancreatic fibrosis. In our previous study(Molecular Therapy 200814) showed that interferon α, by decreasing TGF-βcan significantlyameliorate liver cirrhosis. Therefore, in this study, we will test to use interferon αtreatment ondesmoplastic pancreatic carcinoma xenograft (models established in previous another study,Journal of Hepatology 20098) to determine if IFN-α treatment can provide antistromal effectin a mouse model of pancreatic cancer.胰臟癌纖維化間質幹細胞Pancraetic cancerfibrosisstromal stem cells