臺灣博碩士論文加值系統

惡性腫瘤已連續40年居國人十大死因首位，其中大腸癌是惡性程度最高的癌症之一，有文獻報告指出為世界死亡原因的第二大主因。慢行炎症是結腸癌的主要因素之一，結腸粘膜為構成關鍵屏障和免疫調節的主要部位，免疫系統在癌症的發展和治療中起著重要作用。兒茶素 (EGCG)是一種強大的抗氧化劑，可防止健康細胞發生氧化損傷，也可作為抗血管生成劑和抗腫瘤劑以及腫瘤細胞對化療反應的調節劑。由於先前大腸癌研究多為癌細胞實驗或是著重於結腸炎探討，因此本研究主旨在於利用兩種大腸癌動物模式探討兒茶素 (EGCG) 可否藉抗氧化、抗發炎相關機制以及調節腸道菌群而達到抗癌功效。兒茶素進行成分分析，EGCG 含量為142.32 ppm，總酚含量為 233.57 mg；細胞實驗結果顯示對小鼠 CT-26 結腸癌細胞及倉鼠腎細胞 BHK 具有毒殺性，但在一定濃度下對倉鼠腎細胞 BHK 不具有毒殺性，表明 EGCG 具有保護腎細胞與毒殺癌細胞的效果。以 LPS 誘導小鼠巨噬細胞產生過量一氧化氮 (Nitric oxide, NO) 模擬體外發炎反應，結果顯示EGCG 能夠有效抑制 NO 及發炎細胞因子 IL-6 的產生。將 BALB/c 小鼠以皮下注射小鼠結腸癌細胞探討在腫瘤微環境中之炎症以及免疫調節的效果，由於大腸癌患者會影響到營養吸收，此模型表現惡病質現象評估其減緩能力，結果顯示給予EGCG後可降低腫瘤重量與體積，減緩體重與食慾下降、以及惡病質所造成之肌肉與脂肪流失，並可以降低血液中發炎相關白血球比例、提升免疫中 T 細胞及 NK 細胞及降低 IL-6、TNF-α 及 IL-1β 發炎細胞激素表現量，在腫瘤組織中發現能夠藉由抑制 COX-2 進而減少VEGF 來改善血管新生，並透過調控細胞凋亡及抗凋亡因子 BAX、BCL-2 的表現而抑制腫瘤生長之功效，在此模型所看到的是透過攝食入來免疫調節對癌細胞攻擊並改善全身性炎症。再來以 AOM/DSS 化學誘導所建立大腸原位癌模型，所看到的是腸道癌化的情況，同樣也有抑制息肉生長且對腸道炎症細胞浸潤具有改善的效果，由於此模型較貼近於模擬人患大腸癌情形，在血液分析結果中觀察到能口服EGCG 後能改善大腸癌貧血問題，表示 EGCG 具有抑制腸道發炎及相關癌變的潛力。在腸道菌相中，觀察在給予 EGCG 過程中透過代謝循環改變腸道菌相去影響腸道健康度，在腸道分析上發現在給予 EGCG 過程後能夠提升有益菌並降低 AOM/DSS組中致病菌的產生，同時增加短鏈脂肪酸產量，綜合上述，期望在未來應用上具有開發成改善結腸癌症狀保健食品之潛力。

Malignant tumors have been the top ten causes of death in Taiwan for 40 consecutive years, among them, colorectal cancer is one of the most malignant cancers, and some literature reports point out that it is the second leading cause of death in the world. The colonic mucosa is the main site that constitutes a key barrier and immune regulation., the immune system plays an important role in the development and treatment of cancer. Catechins (EGCG) is a powerful antioxidant that protects healthy cells from oxidative damage and acts as an antiangiogenic and antineoplastic agent. Since previous studies on colorectal cancer were mostly cancer cell experiments or focused on colitis, the main purpose of this study was to explore whether Catechins can achieve anti-cancer effects by comparing two animal models through anti-oxidation and anti-inflammation related mechanisms. Catechins was determined by component analysis, the EGCG content in the sample was 142.32 ppm and the total phenol content was 233.57 mg. The results of cell experiments show that it is toxic to mouse CT-26 colon cancer cells and hamster kidney cell BHK, but it is not toxic to hamster kidney cell BHK at a certain concentration, indicating that EGCG has the effect of protecting kidney cells and killing cancer cells. LPS induced mouse macrophages to produce excess nitric oxide (Nitric oxide, NO) to simulate the inflammatory response in vitro, and the results showed that EGCG could effectively inhibit the production of NO and inflammatory cytokine IL-6. BALB/c mice were subcutaneously injected with mouse colon cancer cells to investigate the effect of inflammation and immune regulation in the tumor microenvironment. Since colorectal cancer patients will affect nutrient absorption, this model exhibits cachexia phenomenon to evaluate its mitigation ability. The results show that Administration of EGCG can reduce tumor weight and volume, slow down weight and appetite loss, and muscle and fat loss caused by cachexia, and can reduce the proportion of inflammation-related white blood cells in the blood, increase immune T cells and NK cells, and reduce IL-6, TNF -α and IL-1β inflammatory cytokine expression, and found in tumor tissue that it can reduce VEGF to improve angiogenesis by inhibiting COX-2, and regulate apoptosis and anti-apoptotic factors BAX, BCL-2 The effect of inhibiting tumor growth, as seen in this model, is through the ingestion of immune regulation to attack cancer cells and improve systemic inflammation. Next, the colorectal carcinoma in situ model was established by AOM/DSS chemical induction. What we saw was intestinal canceration, which also inhibited the growth of polyps and improved the infiltration of intestinal inflammatory cells. Because this model is closer to In the simulation of human colorectal cancer, it was observed in the results of blood analysis that oral administration of EGCG can improve the anemia of colorectal cancer, indicating that EGCG has the potential to inhibit intestinal inflammation and related carcinogenesis. Then use this model to explore the intestinal flora, and observe that the intestinal flora can be changed through the metabolic cycle to affect the intestinal health during the administration of EGCG. In the intestinal analysis, it is found that the beneficial bacteria can be increased and AOM/DSS can be reduced after the administration of EGCG The production of pathogenic bacteria in the group, while increasing the production of short-chain fatty acids, combined with the above, is expected to have the potential to be developed as a health food for improving colon cancer symptoms in future applications.

謝誌 III
摘要 I
Abstract II
圖目錄 VIII
表目錄 X
壹、緒論 1
貳、文獻回顧 3
一、癌症的起源 3
二、大腸癌 (Colorectal cancer) 3
1. 大腸癌簡介 3
2. 大腸癌病理學 4
3. 大腸癌流行病學 5
4. 現今大腸癌治療方式 6
三、囓齒動物大腸癌 7
1. 同種移植 (Allogeneic Model) 7
2. 異種移植 (Xenograft Model) 8
3. 誘發模型 8
3-1. DMH機制 9
3-2. AOM 機制 9
3-3. AOM+DSS機制 9
3-4. AOM+DSS誘導大腸癌模型 10
四、炎症性免疫反應 10
五、癌症惡病質 (Cancer cachexia) 11
六、茶 (Tea) 12
1. 茶 (Tea) 簡介 12
2. 兒茶素 (EGCG) 錯誤! 尚未定義書籤。
3. 兒茶素 (EGCG)的生物活性 13
七、腸道微生物 (Gut microbiome) 14
1. 腸道菌相介紹 14
2. 腸道微生物與大腸癌關係 14
3. 腸道微生物與兒茶素 (EGCG)之關係 15
4. 短鏈脂肪酸 (Short-Chain Fatty Acids, SCFA) 15
4-1 短鏈脂肪酸介紹 15
叁、實驗設計流程 18
一、兒茶素 (EGCG)特性分析 18
二、細胞實驗 18
三、動物實驗 18
肆、實驗材料與方法 22
1. 樣品原料 23
2. 誘導腸癌之化學品 23
3. 抗氧化試驗 23
4. 實驗細胞株 23
5. 細胞培養之培養基 24
6. 細胞存活率試劑 24
7. 一氧化氮 (NO) 生成試驗 24
8. 實驗動物 24
9. 組織切片 25
10. 酵素連結免疫吸附相關試劑 25
11. 免疫細胞分析 25
12. 短鏈脂肪酸及 HPLC 分析藥品 25
二、儀器設備 26
三、實驗方法 27
1. 樣品特性分析 27
1-1. 高效能液相層析法 (High-performance liquid chromatography, HPLC) 27
1-2. 總酚含量測定 (Total phenolic content) 27
2. 兒茶素 (EGCG)之抗氧化能力試驗 27
3. 細胞實驗 (In vitro) 29
3-1. 細胞株活化 29
3-2. 細胞株之培養 (Cell culture) 29
3-3. 細胞株保存 30
3-4. 細胞毒性測試 (Cytotoxicity test) 30
3-5. 細胞內一氧化氮 (Nitrate oxide, NO) 含量測定 31
3-6. 細胞激素分析 31
4. 動物實驗 (In vivo) 32
4-1大腸癌小鼠之動物模式建立 32
4-2 血液分析 32
4-3 免疫細胞分析 32
4-4 病理組織切片分析 33
4-5 抽取小鼠糞便之 DNA（Stool DNA extraction） 34
4-6 短鏈脂肪酸分析 35
5. 統計分析 37
伍、結果 38
一、 兒茶素 (EGCG)特性分析 38
1-1、兒茶素 (EGCG)樣品特性 38
1-2、兒茶素 (EGCG)抗氧化活性之探討 38
1-3、兒茶素 (EGCG)對不同細胞之存活率影響 39
二、 兒茶素 (EGCG)對小鼠巨噬細胞之抗發炎能力分析 39
2-1、兒茶素 (EGCG)對於 RAW264.7 產生一氧化氮 (NO) 之影響 39
2-2、兒茶素 (EGCG)對LPS 誘導之 RAW264.7 生成發炎相關細胞因子之影響 40
三、兒茶素 (EGCG)對大腸癌動物模式之探討 40
3、皮下注射大腸癌細胞之動物模式 41
3-1、兒茶素 (EGCG) 減緩皮下注射大腸癌細胞小鼠之惡病質現象 41
3-1-1、兒茶素 (EGCG)對皮下注射大腸癌細胞小鼠體重變化之影響 41
3-1-2、兒茶素 (EGCG)對皮下注射大腸癌細胞小鼠攝食量之影響 41
3-1-3、兒茶素 (EGCG)對皮下注射大腸癌細胞小鼠肌肉及脂肪之影響 42
3-2 、兒茶素 (EGCG) 對皮下注射大腸癌細胞小鼠減緩體內發炎反應之效果 42
3-2-1、兒茶素 (EGCG)對皮下注射大腸癌細胞小鼠血液生化指數之影響 42
3-2-2、兒茶素 (EGCG)對皮下注射大腸癌細胞小鼠脾臟之影響 43
3-2-3、兒茶素 (EGCG)對皮下注射大腸癌細胞小鼠抑制腫瘤生長之能力 43
3-3、兒茶素 (EGCG)對皮下注射大腸癌細胞小鼠調節免疫細胞之能力 44
3-4、兒茶素 (EGCG)對皮下注射大腸癌細胞小鼠體內促發炎細胞激素之影響 44
3-5. 兒茶素 (EGCG)對皮下注射大腸癌細胞小鼠之腫瘤中COX-2之影響 45
3-5. 兒茶素 (EGCG)對皮下注射大腸癌細胞小鼠腫瘤血管新生之影響 45
3-6. 兒茶素 (EGCG)對皮下注射大腸癌細胞小鼠細胞凋亡相關因子之影響 45
4、化學誘導大腸癌小鼠之動物模式 46
4-1、兒茶素 (EGCG)對 AOM/DSS 化學誘導大腸癌小鼠體重變化、攝食量之影響 46
4-2、兒茶素 (EGCG)對 AOM/DSS 化學誘導大腸癌小鼠之腸道長度、息肉之影響 47
4-3、兒茶素 (EGCG) 對AOM/DSS化學誘導大腸癌小鼠減緩體內發炎反應之效果 47
4-3-1、兒茶素 (EGCG)對AOM/DSS化學誘導大腸癌小鼠血液生化指數之影響 47
4-3-2、兒茶素 (EGCG)對 AOM/DSS 化學誘導大腸癌小鼠體內促發炎細胞激素之影響 48
4-4、兒茶素 (EGCG)對 AOM/DSS 化學誘導大腸癌小鼠調節免疫細胞之能力 48
4-5、兒茶素 (EGCG)對 AOM/DSS 化學誘導大腸癌小鼠腸道 H&E 染色 49
4-6、兒茶素 (EGCG)對 AOM/DSS 化學誘導大腸癌小鼠腸道免疫組織化學染色 49
4-7、兒茶素 (EGCG)對 AOM/DSS 化學誘導大腸癌小鼠腸道菌相中短鏈脂肪酸之影響 50
陸、討論 52
一、 兒茶素 (EGCG)成分與生理活性 52
二、兒茶素 (EGCG)體外實驗 53
2-1、 探討兒茶素 (EGCG)對於小鼠大腸癌細胞 (CT26.WT) 及 倉鼠腎細胞 (BHK-21) 之影響 53
2-2、 探討兒茶素 (EGCG)對於 LPS 誘導 RAW264.7產生 NO量之影響 54
三、兒茶素 (EGCG)對於大腸癌動物模式之影響 55
3-1、兒茶素 (EGCG)抑制腫瘤生長及抗發炎能力 55
3-2、兒茶素 (EGCG)改善癌症惡病質之能力 55
3-3、兒茶素 (EGCG)調節免疫細胞之能力 57
3-4、兒茶素 (EGCG)對炎症環境中促發炎細胞因子之影響 57
3-5、兒茶素 (EGCG)對腫瘤侵襲和血管生成的抑制作用 58
3-6、兒茶素 (EGCG)改善原位癌體重不穩定及食慾問題 59
3-7、兒茶素 (EGCG)改善原位癌之病徵 59
3-8、兒茶素 (EGCG) 改變腸道中短鏈脂肪酸含量 62
柒、結論 64
捌、參考文獻 65
玖、圖 75

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