臺灣博碩士論文加值系統

腫瘤細胞必須要能逃避免疫系統的攻擊，並在新的組織中生存才能造成轉移。雖然腫瘤轉移的機制尚未清楚，不過目前已知有些腫瘤細胞會表現FasL來造成帶有Fas的免疫細胞的細胞凋亡，稱為「Fas的反擊」(Fas counterattack)。本實驗室先前的研究發現降低小鼠黑色素瘤細胞(B16F10)表面FasL的表現，確實減少皮下腫瘤的形成。然而我們卻發現降低FasL的表現，竟然增加了腫瘤轉移至肺臟的機會。本研究希望釐清FasL如何影響黑色素瘤細胞的轉移能力。首先我的研究再次確認利用ribozyme降低FasL的表現，能增加腫瘤在小鼠肺臟的轉移。而且在平面培養的條件之下，降低FasL的表現會增強細胞的移動能力。同時在多細胞腫瘤球體的立體結構系統中，降低FasL的表現也會使細胞脫離腫瘤球體及移動能力增強。但是若降低Fas的表現，細胞移動能力及轉移能力會下降。此外細胞內Fas傳遞訊息下游的caspase cascade的活化並未因FasL的表現而不同，而且抑制caspase-3/8 的活化，也不影響細胞的移動。因此Fas-associated caspase cascade及相關的訊號傳遞調控B16F10細胞移動能力的方式與FasL不同，初步排除改變FasL是透過Fas訊息的降低而影響細胞移動及轉移的可能性。另外，抑制FasL的表現會增加腫瘤細胞中MAPKs的表現。在MAPKs抑制物的存在下，細胞移動的能力會減緩。而且抑制FasL的表現增加細胞FAK的活化，可能因而影響細胞移動能力。此外，在立體腫瘤球體細胞回貼的實驗分析中，FasL會抑制gelatinase被基質激發的速率。FasL影響MMPs的表現可能是FasL改變細胞自腫瘤球體脫落程度的原因。總之，本實驗認為FasL可能具有一個傳遞reverse signal的能力，抑制腫瘤細胞的轉移。

Tumor cells escaping from immune surveillance and surviving in a new tissue environment are important for tumor metastasis. The mechanisms involving in these processes are still not completely understood. Fas/FasL mediated apoptosis is one of the strategies for immune escape. Some FasL-expressing tumor cells induce apoptosis in cytotoxic lymphocytes by direct “ Fas counterattack”. Apoptosis-resistant tumor cells may have enhanced motility and invasiveness upon FasL stimulation. In order to investigate how FasL affect tumor metastasis, we established B16F10-derived cells expressing different levels of Fas or FasL and their metastasis abilities were tested in a pulmonary metastatic animal model. We found that down-regulation of FasL obviously increased lung metastasis of B16F10 in B6 mice. Besides, both up-regulation and down-regulation of Fas reduced lung metastasis. Down-regulation of FasL (R and R149 cells) increased cell motility in 2-D culture, and expressed more activation of ERK and p38. Moreover, down-regulation of FasL increased cells detachment from tumor spheroid, and secreted more metalloproteinase. ERK and p38 inhibitors could reduce cell motility, suggested that ERK and p38 were involved in cell migration. However, the FasL-associated cell migration was caspase-8/3 independent. Down-regulation of Fas reduced cell motility and metastasis provided evidence that Fas signal enhances migration and metastasis, which is different from the effect of FasL. In summary, our results suggested that FasL might trigger novel signaling to inhibit metastasis.

中文摘要……………………………………………………… Ⅰ
英文摘要……………………………………………………… Ⅱ
目錄…………………………………………………………… Ⅲ
圖目錄………………………………………………………… Ⅶ
第1章 序論………………………………………………… 1
1.1 Fas與Fas ligand的作用………………………… 1
1.2 轉移性黑色素細胞癌……………………………… 3
1.3 腫瘤轉移機制……………………………………… 3
1.4 腫瘤轉移與FasL 之相關性……………………… 5
1.5 體外腫瘤細胞球體培養系統 (spheroid system)… 5
第2章 實驗目的及設計 ……………………………………… 7
2.1 實驗目的…………………………………………… 7
2.2 實驗設計…………………………………………… 8
第3章 實驗材料與方法 ……………………………………… 10
3.1 實驗材料…………………………………………… 10
3.1.1 儀器設備…………………………………………… 10
3.1.2 試劑………………………………………………… 10
3.1.3 細胞培養材料……………………………………… 12
3.1.4 抗體………………………………………………… 12
3.2 實驗方法 …………………………………………… 13
3.2.1 細胞株來源與培養………………………………… 13
3.2.2 質體DNA之建構、轉染與細胞株篩選 …………… 13
3.2.3 反轉錄聚合酶連鎖反應…………………………… 14
3.2.4 動物實驗及組織處理……………………………… 16
3.2.5 腫瘤球體的養成與觀察…………………………… 16
3.2.6 冷凍切片技術……………………………………… 17
3.2.7 蘇木紫與伊紅染色法……………………………… 18
3.2.8 細胞蛋白質抽取…………………………………… 18
3.2.9 蛋白質濃度定量…………………………………… 18
3.2.10 西方點墨法………………………………………… 18
3.2.11 SDS-PAGE gelatin zymography assay ………… 21
3.2.12 單一細胞移動分析………………………………… 22
3.2.13 傷口瘉合分析……………………………………… 22
3.2.14 細胞脫離團塊及移行分析………………………… 23
3.3 試劑製備 …………………………………………… 23
3.3.1 細胞株來源與培養………………………………… 23
3.3.2 質體DNA之建構、轉染與細胞株篩選 …………… 24
3.3.3 反轉錄聚合酶連鎖反應…………………………… 24
3.3.4 動物實驗及組織處理……………………………… 25
3.3.5 腫瘤球體的養成與觀察…………………………… 25
3.3.6 冷凍切片技術……………………………………… 25
3.3.7 蘇木紫與伊紅染色法……………………………… 26
3.3.8 細胞蛋白質抽取…………………………………… 26
3.3.9 蛋白質濃度定量…………………………………… 26
3.3.10 西方點墨法………………………………………… 26
3.3.11 SDS-PAGE gelatin zymography assay ………… 28
第4章 實驗結果 ……………………………………………… 30
4.1 小鼠黑色素瘤細胞 B16F10穩定細胞株的建立及確
認腫瘤細胞株FasL表現量……………………………………… 30
4.2 B16F10腫瘤肺臟轉移之動物模式………………… 30
4.3 平面培養時，FasL對於細胞移行能力之影響…… 31
4.4 腫瘤球體的養成及觀察…………………………… 32
4.5 立體培養時，FasL對於腫瘤細胞自球體脫離及細胞
移行能力之影響………………………………………………… 33
4.6 Caspase cascade並未參與FasL調控B16F10細胞的
移動能力………………………………………………………… 34
4.7 Caspase cascade並未參與FasL調控B16F10細胞自
腫瘤球體脫離的能力…………………………………………… 34
4.8 ERK及p38參與FasL調控B16F10細胞的移動能力… 35
4.9 細胞黏著分子( focal adhesion molecules)的表現…36
4.10 ERK參與FasL調控B16F10細胞自腫瘤球體脫離的能力…
……………………………………………………………………… 37
4.11 Matrix metalloproteinases (MMPs)的表現……… 38
4.12 調控Fas的表現不會促進B16F10細胞的移動及轉移… 38
第5章 討論……………………………………………………… 40
第6章 結論……………………………………………………… 44
第7章 參考文獻………………………………………………… 45
附錄 ……………………………………………………………… 52
圖 (Figures) …………………………………………………… 55

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