通络活血虫类中药通过mTOR信号通路对乏氧环境肺癌转移的干预作用研究

To prevent and blocking tumor metastasis is the key to success of the lung cancer threatment, and is the focus and difficulty of its research at home and abroad as well. Our prophase work has initially proved that, formation of lung cancer metastasis is directly related to the phenomenon of "collateral stasis" commonly existed in lung cancer patients, and lung cancer "collateral disease" may be the central link of its metastasis, in which tumor hypoxic microenvironment has the crucially important effect.Basic to the theory of "Worm and ant dredging collaterals" of traditional Chinese medicine, we put forward a working hypothesis that Chinese medicine of worms possessed of dredging collaterals and activating blood function can intervene lung cancer metastasis by the effect on mTOR/HIF-1α /VEGF signal transduction pathway intervention angiogenesis in the hypoxic tumor microenvironment.We intend to use the different growth stage of lung cancer in mice and hypoxia workstation cultured lung cancer cells in vitro and in vivo, respectively simulated hypoxic tumor microenvironment.To observation：①The effects of the three typical insects drugs-Scorpion,Centipede,Shougong on growth and metastasis of lung cancer.② The effects on the mTOR signal transduction pathway related protein phosphorylation;③The effects on tumor HIF-1α and angiogenesis related cytokines expression.We want to explain the correlation between tumor hypoxia micro environment, angiogenesis and metastasis and its"collateral stasis"state. And We wantto definite the specific effect target of insects, expecting to proviod new scientific proofs for insects dredging lung cancer metastasis in clinical work and to further deepening the theory of lung cancer "collateral disease" of Chinese medicine.

防止和阻断转移是肺癌治疗取得成功的关键，前期工作证实，肺癌转移与患者普遍存在的"络脉瘀滞"现象有直接关系，"络病"可能是肺癌发生转移的中心环节，乏氧微环境在这一过程中起着至关重要的作用。基于传统中医"虫蚁通络"理论，我们提出通络活血虫类中药可能通过影响肿瘤乏氧微环境中的mTOR/HIF-1α/VEGF信号传导通路干预肿瘤血管生成从而影响肺癌转移的工作假说，拟运用不同生长转移阶段小鼠肺癌和低氧工作站培养肺癌细胞分别在体内、外模拟肿瘤乏氧微环境，观察：①全蝎、蜈蚣、守宫3味虫类代表药对肺癌生长转移的影响；②对mTOR信号转导通路相关蛋白磷酸化的影响；③对肿瘤HIF-1α及血管生成相关因子表达水平的影响，以期阐释肿瘤乏氧微环境、血管生成及转移与其"络脉瘀滞"状态的相关性，明确虫类药在的改善肿瘤乏氧方面的具体作用靶点，为临床合理应用虫类药干预肺癌转移提供科学依据，进一步深化中医肺癌"络病"理论。

防止和阻断转移是肺癌治疗取得成功的关键，前期工作证实，肺癌转移与患者普遍存在的“络脉瘀滞”现象有直接关系，“络病”可能是肺癌发生转移的中心环节，乏氧微环境在这一过程中起着至关重要的作用。基于传统中医“虫蚁通络”理论，我们提出通络活血虫类中药可能通过影响肿瘤乏氧微环境中的mTOR/HIF-1α/VEGF信号传导通路干预肿瘤血管生成从而影响肺癌转移的工作假说，拟运用不同生长转移阶段小鼠肺癌和低氧工作站培养肺癌细胞分别在体内、外模拟肿瘤乏氧微环境，观察：①全蝎、蜈蚣、守宫3味虫类代表药对肺癌生长转移的影响；②对mTOR信号转导通路相关蛋白磷酸化的影响；③对肿瘤HIF-1α及血管生成相关因子表达水平的影响，以期阐释肿瘤乏氧微环境、血管生成及转移与其“络脉瘀滞”状态的相关性。. 实验结果初步显示，通络活血虫类中药可抑制小鼠LL/2-luc-M38肺癌生长和转移，其作用机理与其对肺癌HIF-1α及mTOR信号转导通路的干预作用相关。本研究结果为临床合理应用虫类药干预肺癌转移提供了科学依据，进一步深化了中医肺癌“络病”理论。我们今后还需针对本实验结果开展进一步的研究。