2014-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644420摘要：肺癌是全世界癌症死因前幾名，也是台灣癌症死因的第一名。學界發展許多治療方式， 包括化學治療，是想提高肺癌的治癒率。然而，癌細胞能藉由許多已知或未知的方式產 生抗藥性。最近癌幹細胞的理論，可以用來解釋腫瘤的異質性，腫瘤的發生及抗藥性的 產生。癌幹細胞的理論源自 '幹細胞〃，而幹細胞的維持需要靠周圍的微環境。癌幹細 胞周圍的環境，也有維持癌幹細胞特性的能力。在我們之前的研究-癌症相關纖維母細 胞（Cancer-associated fibroblast , CAF)可以藉由旁分泌（paracrine effect)維 持肺癌細胞的癌幹細胞特性。而肺癌幹細胞也能將正常的纖維母細胞（Normal fibroblast, NF)轉化成為CAF。接下來的兩年，我們將延續之前的研究，針對NF如 何被轉化成CAF，比較NF及CAF的型態、特性、基因表現及DNA曱基化的差異。另一 個主軸是阻斷CAF及癌幹細胞的交互作用，研究是否能降低癌幹細胞的特性，進而降低 抗藥性。目標：一、研究CAF的特性：比較NF及CAF的差異並找出NF轉化成CAF的機制。二、阻斷CAF的旁分泌作用，降低癌幹細胞的特性，進而減少癌細胞的抗藥性。藉由 genome 及 epigenome 高通量分析，包括 cDNA、DNA Methylation、miRNA array，分析CAF維持癌幹細胞的機制，進而找出阻斷機制的方法，可以增加癌細胞對 藥物的敏感度。另外，NF如何轉化成CAF，如果能反轉這個機制，或是抑制CAF旁分泌的作用，也 可以用來減少癌細胞的抗藥性。<br> Abstract: Lung cancer is the leading cause of death worldwide including Taiwan. Systemic therapies have been widely developed to improve cure rate of lung cancer. However, cancer cells can acquire resistance to corresponding treatments by several known/unknown mechanisms. Among them, the cancer stem cells (CSCs) theory has been proposed to explain tumor heterogeneity, the process of carcinogenesis and drug resistance. Microenvironment or “niche” is important for the maintenance of normal stem cells. It is suggested that niche of CSCs has a similar role as that of normal stem cells to maintain the stemness of cancer cells. And our previous study showed that cancer-associated fibroblasts (CAFs) could maintain stemness of lung cancer cells through numerous paracrine effects. Lung CSCs could also educate the normal fibroblasts (NFs) to become CAFs. In the next two years, we will continue our previous study and focus on the functional study of CAFs. According to the published data, CAFs obtain more advanced ability, compared to NFs, to promote cancer stemness and tumorigenesis but the mechanisms of how NFs are educated to become CAFs are still unknown. Our goals are to compare the differences of NFs and CAFs in terms of their morphologies, phenotypes, gene expression and DNA methylation, and to examine the underlying mechanisms of the transformation between them. We will also try to interrupt the interaction between lung CSCs and CAFs and try to decrease the stemness of lung CSCs. We hope to overcome drug resistance by decreasing cancer stemness through blocking the interaction of lung CSCs and CAFs.Specific aim:1.To characterize the cancer associated fibroblasts (CAFs): We will compare the differences between normal fibroblasts (NFs) and CAFs and clarify the mechanisms of how NFs are educated to become CAFs.2.To verify and further block the paracrine effects of CAFs to suppress stemness of lung cancer cells and to find the possible mechanisms for overcoming drug resistance.Objectives: The goal of this study is to find the mechanisms of how CAFs maintain stemness of cancer cells by genome and epigenome-wide high-throughput analysis, including cDNA array, DNA methylation array and miRNA array. Following that, we will try to block the interacting pathway(s) to decrease the stemness of cancer cells and thus, to increase drug sensitivity. Furthermore, CAFs and cancer cells co-culture systems could be used to screen candidate drugs. This methodology will be better than the screening of drugs through cancer cells only.In the next two years, we will focus on the CAFs studies, including the mechanisms of their transformation from NFs and the blockade of the interaction between CAFs and cancer cells, especially through inhibiting paracrine effects of CAFs. If we can stop the transformation from NFs to CAFs or block the paracrine effects of CAFs, we might be able to decrease the stemness of lung cancer cells and increase drug sensitivity during treatment. It will be a novel way to overcome drug resistance and might be a good target for pharmaceutical design.肺癌癌幹細胞微環境癌症相關纖維母細胞旁分泌Lung cancercancer stem cellmicroenvironmentcancer associated fibroblastparacrine effect