从免疫衰老与循环肿瘤细胞揭示肺癌发病及转移核心病机“正虚伏毒”的形成机制

Lung cancer mortality ranks first among various types of malignancies and the prevention of its occurrence and metastasis is the key to lower its death rate. According to TCM theoretical system, kidney Qi in our body begins to decline since the age of 40, which leads to high incidence of lung cancerand in light of our clinical and basic research on immunosenescence and circulating tumor cells (CTC) of lung cancer, we propose a hypothesis that “the biological foundation for “declined healthy Qi and hidden poison”, the principal pathogenesis of the occurrence and metastasis of lung cancer, is the peripheral immune suppression and CTC mediated by immunosenescence. Several steps have been taken to verify the hypothesis. First, the model of lung cancer occurrence is established by inoculating low-dose lung cancer cells in lung in situ based on the mice immunosenescence induction. Then the microenvironment of lung tumor immunosuppression, peripheral blood immunosuppressive state as well as the functions of CTC promoting lung cancer occurrence and metastasis are dynamically evaluated with lung tumor rate and lung metastasis rate as its main indicators. Furthermore, Jinfukang Oral Liquid, the functions of which are to strengthen the body resistance and dispel the poison, is taken to intervene the core pathogenesis of “declined healthy Qi and hidden poison” to verify the hypothesis. From this we hope to reveal the biological foundation of “declined healthy Qi and hidden poison” from the perspectives of peripheral immunosuppression and CTC mediated by thymus epithelial cell inducing immunosenescence, and centering on this, we are going to expound on the mechanism of principal pathogenesis and the molecular mechanism of Jinfukang Oral Liquid preventing the occurrence and metastasis of lung cancer. The result of the study will innovate the pathogenesis theories of lung cancer occurrence and its metastasis, promote the research on lung cancer prevention, and enrich the theoretical connotation of preventative treatment of disease.

肺癌死亡率仍高居恶性肿瘤首位，预防发生和转移是降低死亡率的关键。根据肺癌在“五八（40岁），肾气衰”后的高发特点，结合我们对免疫衰老和肺癌循环肿瘤细胞的临床与基础研究发现，提出“免疫衰老介导的外周免疫抑制与循环肿瘤细胞是肺癌发病及转移核心病机‘正虚伏毒’生物学基础”的假说。为验证该假说，首先诱导小鼠免疫衰老基础上肺原位接种小剂量肺癌细胞建立发病模型；然后以肺部成瘤率和肺转移率为主要指标，动态评估肺部肿瘤免疫抑制微环境、外周血免疫抑制状态和CTC促进肺癌发病和转移的作用；进而采用具有“扶正蠲毒”作用的金复康口服液干扰“正虚伏毒”的核心病机以验证。课题将分别从胸腺上皮细胞诱导免疫衰老介导外周免疫抑制和循环肿瘤细胞角度揭示“正虚伏毒”的生物学基础，阐明核心病机的形成机制和金复康预防肺癌发病和转移的分子机制。课题顺利完成将创新肺癌发病和转移的病机理论，推进肺癌防治研究，丰富“治未病”理论的内涵。

肺癌是导致癌症患者死亡人数最高的恶性肿瘤。预防肺癌的发生和转移是降低死亡率的关键。衰老介导的免疫衰老是造成肺癌发生和转移的重要因素。根据肺癌在“五八（40岁），肾气衰”后高发的特点，我们提出了“免疫衰老介导的外周免疫抑制与循环肿瘤细胞是肺癌发病及转移核心病机‘正虚伏毒’生物学基础”的假说，并开展了免疫衰老对肺癌转移的影响，以及扶正中药金复康调控免疫衰老预防肺癌转移发生的研究。结果发现自然衰老的小鼠具有免疫衰老的特性，以及在衰老小鼠的体内展示出慢性炎症反应。此外，具有免疫衰老特征的小鼠可显著的促进肺癌细胞的转移。进一步的研究发现具有扶正作用的中药复方金复康具有延缓小鼠免疫衰老，抑制肺癌转移的作用。机制研究发现金复康可促进外周血中巨噬细胞向M2型分化，以及可以促进肺转移灶内NK细胞的浸润。进一步研究发现金复康可逆转D-半乳糖诱导的免疫衰老小鼠的胸腺氧化损伤。本研究初步揭示了“正虚”的本质——免疫衰老与转移发生之间的关系，明确了扶正中药改善“正虚”防治肺癌转移发生的作用与机制，验证了“正虚伏毒”理论在肺癌发生和转移防治中的重要作用，丰富了“扶正治癌”理论的科学内涵。