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姓名	謝忻玲(Hsin-Ling Hsieh)  查詢紙本館藏	畢業系所	化學工程與材料工程學系
論文名稱	抗癌藥物的鑑定性用於分析大腸癌中癌幹細胞之研究 (Evaluation of Anti-cancer Drugs for Colon Cancers by Analyzing the Population of Cancer Stem Cells)
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摘要(中)	在西家裡，大腸癌是高居第二死亡率，且一半以上的病人在五年內死於其併發症。本研究利用人類大腸癌細胞株LoVo，培養在不同濃度之治癌藥物和含有血清之培養基裡。隨著治癌藥物濃度的提高，細胞裡的腫瘤胚胎抗原(CEA)濃度隨之增加；尤其，在高濃度之綜合抗癌藥物組合(FLOX)下，癌細胞密度隨之降低，但每一個癌細胞之腫瘤胚胎抗原釋放量是控制組的一百倍。顯示出大腸癌細胞，如 LoVo 和 CW2，利用抗癌藥物抑制(如阿斯匹靈)其生長過程，可有效提高癌細胞對腫瘤胚胎抗原的分泌量。 癌幹細胞是被定義為一群具有導致腫瘤性生長的少量癌細胞；因此，只有少數的大腸癌細胞(大腸癌幹細胞)能使腫瘤生長。在腦瘤和大腸癌中，藉由標記抗體CD133分辨並純化出癌幹細胞，其標記抗體也表現於原始細胞，如神經細胞、造血細胞、上皮和內皮細胞等細胞譜系。我們觀察大腸癌細胞LoVo在不同濃度的抗癌藥物裡癌幹細胞的表現(CD133low弱表現細胞和CD133high強表現細胞)，發現CD133llow弱表現細胞的比率會隨著抗癌藥物濃度的提高而降低；然而CD133high強表現細胞的比率會隨著抗癌藥物的提高而上升，此趨勢相反於回顧文獻中，肺癌細胞的生存率隨著抗癌藥物濃度增高而降低。因此，本研究提出此CD133high強表現性細胞為癌幹細胞或初始性癌細胞的假說。我們也將CD133high強表現細胞與CD133low弱表現細胞用於動物體內實驗來加以佐證上述的假說。 利用高濃度的抗癌藥物(5-FU)來針對大腸癌細胞LoVo，其癌幹細胞的存活率可達14.3%；相較於其他高濃度之抗癌藥物的結果，癌幹細胞的存活率少於或者甚至不到1%。而且複合性抗癌藥物(FLOX、Mayo Clinic、Roswell Park)的結果比起使用單一抗癌藥物還能更有效地降低大腸癌細胞中的癌幹細胞量。本研究提出一套具發展性的有效方法，是為利用抗癌藥物來分析CD133high強表現性的大腸癌幹細胞。
摘要(英)	Colorectal carcinoma is the second leading cause of cancer death in the Western countries with almost 50% of the patients dying for cancer related problems and with a dismal 5-year survival rate. In this study, human colorectal adenocarcinoma tumor (LoVo) cells are cultured in Ham’s media containing 20% fetal bovine serum (FBS) and the different concentrations of anti-cancer drugs. The production of carcinoembryonic antigen (CEA) per cell increased with increase of concentration of anti-cancer drugs in the culture media. Especially, the production of CEA per cell increased by up to one hundred fold compared to cultivation in normal media by adding combination of anti-cancer drugs of FLOX regime (5-FU:LV:OXA=6:6:1) in the culture media, while the cell density decreased by down to 1% of cell survival ratio. It is suggested that colorectal adenocarcinoma tumor such as LoVo cells as well as CW2 cells can produce CEA more effectively when the cell growth is suppressed by addition of toxic chemicals such as aspirin. It is generally recognized that only a few cancer cells are tumorigenic and that these tumorigenic cells could be considered as cancer stem cells (CSCs). Thus, only a small subset of colon cancer cells (i.e., cancer stem cells) is able to initiate tumor growth. Recently CSCs in brain tumor and colon carcinoma can be identified and isolated through the CD133 marker, which is expressed by normal primitive cells of the neural, hematopoietic, epithelial and endothelial lineages. We investigated the population of cancer stem cells (CD133low cells and CD133high cells) in LoVo cells, when the cells were treated with different combination and concentration of anti-cancer drugs. The ratio of CD133low cells (CD133 expressing cells) decreased with the increase of the concentration of anti-cancer drugs, while the ratio of CD133high cells (strong CD133 expressing cells) increased with the increase of the concentration of anti-cancer drugs of which tendency is the opposite to that found in lung cancer cells using cisplatin reported in the literature. We made a hypothesis that CD133high cells should be the cancer stem cells or cancer initiating cells in this study. The tumor generation on NOD mice by injection of CD133low cells and CD133high cells was investigated to verify this hypothesis. Cancer stem cells (CD133high cells) increased with the decrease of cell density by adding concentration of single anti-cancer drug of 5-FU into the culture medium of LoVo cells by up to 14.3% population, while the population of cancer stem cells was found to be less than 1% when combination of anti-cancer drugs was added into the culture medium of LoVo cells. The treatment of combination of anti-cancer drugs (Mayo clinic regime [5-FU:LV=25:1], Roswell Park regime [5-FU:LV=1:1], and FLOX regime [5-FU:LV:OXA=6:6:1]) to colon cancer cells (LoVo cells) was found to be extensively effective to suppress the cancer stem cell population compared to that of single anti-cancer drugs. The present study developed the evaluation method of anti-cancer drugs for cancer therapy by analyzing CD133high population in colon cancer cells.
關鍵字(中)	★ 癌幹細胞 ★ CD133表現 ★ 抗癌藥物	關鍵字(英)	★ Cancer stem cells ★ anti-cancer drugs ★ CD133 expression
論文目次	摘要 i Abstract ii 誌謝 iv Acknowledgement v Index of Contents vi Index of Figures viii Index of Tables xii Chapter 1 Introduction 1 1-1 Introduction 1 1-1-1 Definition of Cancer Stem Cells 1 1-2 Analysis of cancer stem cells 5 1-2-1 Flow cytometry analysis 8 1-2-1-1 Surface marker analysis of stem cells and cancer stem cells 10 1-2-1-2 Purification of CSCs by MACS 13 1-2-2 Anti-cancer therapy (Chemotherapy) 15 1-2-3 In vivo experiment 19 Chapter 2 Materials and Methods 21 2-1 Preparation of normal cell culture 21 2-2 Preparation of anti-cancer drugs culture media 23 2-3 Preparation of buffer solution 25 2-4 Treatment of cells with several anti-cancer drugs 25 2-5 CEA production analysis (contain cell morphology) 26 2-6 CD133 expression of cells measured by flow cytometry 28 2-7 MACS sorting of normal LoVo cell 28 2-8 Tumor generation in vivo 30 2-8-1 Transplantation of Colon Cancer Cells into NOD Mice 30 2-8-2 Immunohistochemistry 31 Chapter 3 Results and Discussion 33 3-1 Morphology of LoVo cells cultured with anti-cancer drugs (Chemotherapy) 33 3-2 CEA production of LoVo cells treated with chemotherapy 45 3-3 Surface marker analysis of cancer stem cell (CSC) 50 3-3-1 Definition of cancer stem cell (CSC) from size of LoVo cell 50 3-3-2 CD133 expression of cancer stem cells treated with anti-cancer drugs 54 3-3-3 Relationship between CEA production and CD133 expression 61 3-3-4 Cancer stem cell (CSC) purified by MACS method from LoVo cells 63 3-4 In Vivo Xenotransplantation Experiment 66 Chapter 4 Conclusion 70 Reference 71 Supplemental data 82
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指導教授	樋口亞绀(Akon Higuchi)	審核日期	2010-7-14
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