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研究生: 黃香萍
Hsing-Ping Huang
論文名稱: 以動物模式探討運動對人類乳癌作用之影響
Effect of exercise on tumor progression - in vitro and in vivo breast cancer model
指導教授: 王鶴森
Wang, Ho-Seng
張嘉銘
Chang, Jia-Ming
學位類別: 博士
Doctor
系所名稱: 體育學系
Department of Physical Education
論文出版年: 2014
畢業學年度: 102
語文別: 中文
論文頁數: 111
中文關鍵詞: 癌症血管新生細胞激素乳酸
英文關鍵詞: cancer, angiogenesis growth factor, cytokines, lactate
論文種類: 學術論文
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  • 雖然流行病學及臨床病學研究皆指出運動可減少罹患某些特定癌症的風險,但運動對癌細胞分子層次的影響及能量代謝的過程仍不清楚。本研究目的首先以細胞模式探討不同濃度之乳酸對人類乳癌細胞MDA-MB-231的影響。不同乳酸濃度加入乳癌細胞中培養,觀察細胞內MCT1、MCT4、CD147及HIF-1α之變化,結果顯示乳酸會造成MCT1、MCT4及HIF-1α蛋白表現下降之趨勢。由此推論乳酸可改變乳癌細胞MCT1、MCT4及HIF-1α之蛋白表現。接下來,以動物模式探討運動對於人類乳癌腫瘤之作用。給予荷腫瘤動物進行中及高強度之跑步機運動,速度設定分別為16 m/min及20 m/min,每次30分鐘,連續28天。結果顯示運動會有抑制腫瘤生長之趨勢,分析來自人類腫瘤分泌之血清血管相關的生長因子17項指標及血清中來自老鼠來源的細胞激素32項指標中,分別有2項和血管新生作用相關之指標及9項血清細胞激素指標之反應和運動強度之作用具相關性,包括抑制腫瘤分泌G-CSF及follistatin之濃度,以及減少血清IL-7、IL-9、IL-12 (p40)、IL-12 (p70)、IL-13、GM-CSF及M-CSF指標之濃度。同時分析腫瘤內MCT1、MCT4、CD147及HIF-1α之蛋白表現,MCT1、MCT4及HIF-1α蛋白表現有下降之趨勢。本研究結論為運動介入可抑制人類腫瘤血管新生相關之生長因子分泌,改變腫瘤之生長養分供給,以及引起小鼠血清細胞激素表達的改變,調節免疫作用及發炎作用,進而造成抑制腫瘤生長之趨勢。另外,由細胞模式可以看出,乳酸造成腫瘤MCT1、MCT4及HIF-1α蛋白表現有下降之趨勢,且在動物實驗中亦發現有相同的結果,顯示乳酸可能會影響腫瘤能量代謝的過程。未來,對於乳癌患者來說,中及高強度運動可能可做為輔助治療癌症的策略之一。

    Recent epidemiologic studies have provided the first observation that regular exercise with moderate intensity is beneficial to cancer patients, but the molecular mechanisms underlying this relationship remain unclear. Therefore, the aim of this study was firstly to investigate the effect of lactate on breast cancer, which is affected by monocarboxylic acid transporter enzymes and hypoxia enzyme such as MCT1, MCT4, CD147 and HIF-1α protein. As a result, it shows a decreasing trend of the protein amount of MCT1, MCT4 and HIF-1α. Secondly, the aim of this study was to investigate the effect of exercise on breast cancer growth in vivo. Mice bearing breast tumor were given middle and high intensity treadmill exercise for 28 days with 30 minutes per day, the speed was set 16 m/min and 20 m/min. Animal study revealed that the development of the tumor on the breast tumor-bearing mice was inhibited during exercise program. Further research shows that human angiogenesis growth factor such as G-CSF, follistatin and mouse cytokine such as IL-7、IL-9、IL-12 (p40)、IL-12 (p70)、IL-13、GM-CSF and M-CSF, were highly correlated with exercise program. The level of MCT1, MCT4 and HIF-1α were also decreased accordingly with the result of lactate-treated breast cancer cells. In conclusion, exercise could inhibit the level of angiogenesis growth factor, change the nutrient supply of tumor growth, thus cause the change of cytokine profiles in inflammatory cytokines and angiogenesis associated cytokines, and further regulate immunological response and inflammation status, thereby inhibit the growth of the tumor. This result implied that the inhibition of tumor growth was mediated by the effect of lactate, which is in accordance with the decrease of MCT1, MCT4 and HIF-1α in vitro and in vivo. For breast cancer patient, it is suggested that middle or high intensity exercise programs could be beneficial for cancer management and act as an adjuvant therapy during cancer treatment.

    口試委員與系主任簽字之論文通過簽名表 i 論文授權書 ii 中文摘要 iii 英文摘要 iv 謝誌 v 目次 vii 表次 x 圖次 xi 第壹章 緒論 1 一、 研究背景 1 二、 研究目的 4 三、 研究假設 5 四、 名詞操作性定義 5 五、 研究限制 7 第貳章 文獻探討 8 一、 癌細胞的能量代謝 8 二、 單羧酸轉運蛋白 (monocarboxylate transporter, MCTs) 與癌症 11 三、 血管新生生長因子與癌症 15 四、 細胞激素與癌症 16 五、 運動與癌症 18 第參章 實驗方法與步驟 28 第一部分:不同濃度之乳酸對人類乳癌細胞的影響 28 一、 人類乳癌細胞培養與處理 28 二、 偵測不同濃度乳酸對人類乳癌細胞存活率及MCT1、MCT4、CD147及HIF-1α蛋白表現之影響 28 三、 細胞蛋白質之萃取 (Protein extraction) 29 四、 西方點墨法 (Western blot) 29 第二部分:以動物模式探討不同強度運動人類乳癌作用之影響 30 一、 動物實驗流程 30 二、 老鼠品系 31 三、 跑步機運動能力測試 31 四、 建立MDA-MB-231人類乳癌小鼠皮下移植瘤模型 31 五、 建立MDA-MB-231人類乳癌小鼠之運動模式 31 六、 血清細胞分析 32 七、 酵素免疫 (enzyme-linked immunosorbent assay, ELISA) 分析 32 八、 資料收集與分析 32 九、 統計分析 33 第肆章 結果 34 第一部分:不同濃度之乳酸對人類乳癌細胞的影響 34 一、 細胞存活率分析法 34 二、 以西方點墨法分析乳酸對乳癌細胞蛋白表現量的影響 36 第二部分:以動物模式探討不同強度運動對人類乳癌作用之影響 37 一、 小鼠每週體重之變化 37 二、 小鼠組織重量之比較 38 三、 小鼠每週腫瘤大小之變化 39 四、 不同強度運動對腫瘤內蛋白表現的影響 41 五、 不同強度運動對患有乳癌之小鼠血球之影響 42 六、 不同強度運動對患有乳癌小鼠之人類血管因子的影響 44 七、 不同強度運動對患有乳癌之小鼠血液細胞激素之影響 46 八、 不同強度運動對患有乳癌之小鼠血乳酸濃度的影響 60 第伍章 討論與結論 61 一、 乳酸對MCT1、MCT4及HIF-1α蛋白表現之影響 61 二、 運動對小鼠每週體重及組織重量之影響 62 三、 運動對小鼠每週腫瘤大小之變化 62 四、 運動對血管新生因子之影響 63 五、 運動對血清細胞激素之影響 64 六、 結論 67 引用文獻 68 附錄 附錄一 不同濃度乳酸對乳癌細胞存活率之影響 92 附錄二 不同強度運動28天對小鼠體重之影響 93 附錄三 不同強度運動28天對小鼠心臟、脾臟、肺臟、肝臟及腎臟重量百分比之影響 94 附錄四 不同強度運動對小鼠每週腫瘤大小之變化 95 附錄五 不同強度運動對小鼠血球之影響 96 附錄六 不同強度運動對小鼠腫瘤分泌之人類血管生長因子的影響 97 附錄七 不同強度運動對小鼠血清細胞激素的影響 98 附錄八 不同強度運動對小鼠血乳酸之影響 99 個人小傳 100

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