以動物模式探討運動對人類乳癌作用之影響

Abstract

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.