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系統識別號 U0026-1408201323582100
論文名稱(中文) 類口腔癌幹細胞與血管新生的研究
論文名稱(英文) A study of angiogenesis and oral cancer stem-like cells
校院名稱 成功大學
系所名稱(中) 口腔醫學研究所
系所名稱(英) Institute of Oral Medicine
學年度 101
學期 2
出版年 102
研究生(中文) 康瑋庭
研究生(英文) Wei-Ting Kang
學號 T46001041
學位類別 碩士
語文別 中文
論文頁數 77頁
口試委員 指導教授-袁國
口試委員-陳玉玲
口試委員-黃振勳
中文關鍵字 癌症幹細胞  人類舌鱗狀細胞癌懸浮球體 
英文關鍵字 cancer stem-like cel  lhuman tongue squamous-cell carcinoma cell (SAS) tumor sphere 
學科別分類
中文摘要 口腔鱗狀細胞癌(OSCC)是口腔頷面部常見的癌症,在全世界10大癌症排行第六名,在亞洲也約有8%到10%的人罹患此癌症。有文獻指出神經膠原母細胞瘤的癌類幹細胞可以分化成功能性的內皮細胞,而內皮細胞在血管新生過程中扮演重要角色,也有文獻發現腫瘤幹細胞在懸浮球體(tumor sphere)中含量較多。血管新生(angiogenesis)在腫瘤生長和轉移時必要的過程,近年來科學家們也發現血管新生和癌症的發展有密切的關係。目前在臨床上發現癌症病患仍會有抗藥性或許給予化療不見得有好轉,甚至不能完全治癒。因此,此篇研究目的想探討腫瘤類幹細胞與血管新生之間的交互作用是否是造成此現象的原因。
一開始先比較人類舌鱗狀細胞癌(SAS)的tumor sphere和單層細胞(monolayer)中幹細胞markers (如: CD133、Nanog、ALDH1A1和Oct4)的表現變化。這些marker在real-time PCR、西方點墨法(western blotting)以及免疫染色(immunostaining)的結果都可以發現懸浮球體的表現量高於單層細胞。之後利用angiogenesis PCR array分析並篩選upregulation的血管新生因子,此因子包括CXCL10(趨序趨化因子10)、CXCL3(趨序趨化因子3)、IL8(白細胞介素8)和TNF(腫瘤壞死因子)。另外也使用細胞分選 (cell sorting)篩選出CD133+ cells,並使用real-time PCR檢測發現CXCL3、IL8、TNF具有高度表現,另外我們也檢測內皮細胞分子標誌 Factor VIII的表現,其實驗結果證實CD133+ cells中Factor VIII表現量比CD133- cells來的高。
以上結果可證明懸浮球體確實具有癌症幹細胞特性。我們也鑑定一些有關腫瘤類幹細胞的血管生成因子(趨化因子)。此研究結果可能有助於在癌症治療上開發新的方法。

英文摘要 Oral squamous cell carcinoma (OSCC), the most common cancer in the oral and maxillofacial region, is the sixth most prevalent type of malignancy worldwide and account for approximately 8% to 10% of all cancers in Asia.
Some studies indicate that tumor sphere has more cancer stem-like (CSCs) cells. Angiogenesis is the propelling force for tumor growth and metastasis. Some cancer patients also accompany drug resistance during treatment, so they have poor prognosis after chemotherapy treatment. A portion of the patients can not be completely cured due to cancer metastasis. Therefore, many researchers highly suspect that cancer stem-like cells and angiogenesis may be the main reasons for this phenomenon.
First, we compared human tongue squamous cell carcinoma (SAS) tumor sphere and monolayer for expression of stem cell genes and related proteins, including CD133, Nanog, ALDH1A1 and Oct4, using quantitative RT-PCR, western blotting, and immunostaining to analyze these stem cell markers expression in tumor sphere. Next, we utilized angiogenesis PCR array to identify up-regulated angiogenic factors. We also confirmed the findings using real-time PCR on cell-sorted CD133+ cells to reconfirm the data.
The levels of CD133, Nanog, ALDH1A1 and Oct4 were up-regulated in tumor sphere compared with monolayer based on quantitative RT-PCR, western blotting and immunostaining. We demonstrated tumor sphere contained more cancer stem-like cell. The data of angiogenesis PCR array identified up-regulation of several angiogenic factors, including CXCL10 (C-X-C motif Chemokine 10), CXCL3 (C-X-C motif Chemokine 3), IL8 (Interleukin 8) and TNF (Tumor nerosis factor). Most of them are chemotactic factors. Cell sorting for CD133+ cells also confirm CXCL3, IL8 and TNF were more expressed in CD133+ cells. We were also examined endothelium cell marker Factor VIII and found that it was more expressed in CD133+ cells.
Our analysis indicated that tumor sphere have cancer stem-like cell characteristics. We identified some upregulated angiogenic factors (chemotactic factors) in cancer stem-like cells. The results may help to develop new cancer therapies.
論文目次 中文摘要 I
Abstract II
致謝 IV
圖目錄 VII
英文縮寫檢索表 VIII
第一章 緒論 1
一、口腔癌概論 1
二、癌症幹細胞(Cancer stem-like cells) 2
1. 癌症與幹細胞與癌症幹細胞 2
2. 癌症幹細胞標誌(cancer stem-like cell markers) 4
三、血管新生(Angiogenesis)概論 6
1. 血管 6
2. 血管新生簡介 7
3. 血管新生在癌症中的作用 8
四、癌症幹細胞和腫瘤血管生成的關係(cancer stem-like cells and Tumor angiogenesis) 8
五、研究動機 10
第二章 實驗材料與方法 12
一、免疫染色 (Immunostaining) 12
二、SDS-PAGE 蛋白質電泳 (SDS-PAGE protein electrophoresis) 15
三、西方點墨法 (Western blot) 16
四、細胞培養 (Cell culture) 18
a. 繼代培養 (Subculture) 19
b. 冷凍保存細胞 (Freezing cells) 19
c. 解凍細胞 (Thawing cells) 20
d. 細胞計數 (Cell counting) 20
五、細胞蛋白質萃取 (Protein extraction) 21
六、蛋白質濃度測定 (Protein assay) 21
七、萃取RNA (RNA extraction) 22
八、反轉錄PCR (RT- PCR) 23
九、即時定量PCR (Real-time PCR) 24
十、血管新生PCR array (Angiogenesis PCR array) 25
十一、慢病毒的製備 (shRNA Lentivirus production) 25
十二、抽取質體 26
十三、洋菜膠體電泳 (Agarose gel electrophoresis) 28
十四、偵測細胞表面接受器 (Cell surface receptor detection) 29
十五、細胞分選 (cell sorting ) CD133+ cells 30
十六、免疫酵素反應 (Enzyme-linked Immunosorbent Assay ; ELISA) 31
十七、培養conditioned medium 34
十八、統計分析 ( Statistics methods ) 34
十九、儀器設備、試劑藥品、套裝試驗組、抗體、耗材 35
第三章 實驗結果 41
一、培養單層細胞(Monolayer)以及貼附型(Adherent)和懸浮型(Suspension)的懸浮球體(Tumor sphere) 41
二、比較體癌症幹細胞標記在Monolayer與Adherent和Suspension的Tumor sphere的表現量 41
三、利用血管新生(Angiogenesis)PCR array找出有upregulation的血管新生相關基因 42
四、利用Real-time PCR再次確認Angiogenesis PCR array upregulation的基因 43
五、分析Adherent sphere和Suspension sphere所含有CD133+的細胞數目 43
六、運用細胞分選 (cell sorting) CD133+ cells和CD133- cells來檢測up-regulation的基因以及Factor VIII是來自於cancer stem-like cells而不是來自於tumor sphere其他非幹細胞 44
七、比較CXCL3、IL8、TNF在monolayer與tumor sphere的表現量 45
第四章 實驗討論 47
第五章 結論 52
參考文獻 53
結果(附圖) 60
附錄一 73
附錄二 76
自述 77

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