基于"治未病"理论探讨葛根散通过SDF-1/CXCR4轴干预结直肠癌肝转移的作用及机制

This research mainly focuses on studying the mechanism of regulating microenvironment of liver and inhibiting liver metastasis of colorectal cancer in mice CT26 colon cancer cells by Gegen Decoction. Over the past decade, 20%-50% of the colorectal cancer patients were found with liver metastasis, and the 5 year survival rate was about 50%.Prevention and inhibiting of liver metastasis is the key factor to decide the prognosis of colorectal cancer. The changes of tumor microenvironment play an important role in the process of tumor invasion and metastasis, therefor, regulating microenvironment of liver may be a new target of inhibiting liver metastasis of colorectal cancer. "Prevention of disease", one of the most influential theories of the traditional Chinese medicine mentioned in the " chai hou fang fu "and "xian an wei shou xie zhi di" which means pre-regulation of the viscera which the disease will be transferred to so as to prevent disease recurrence.so could we use the Chinese medicine to regulate the microenvironment of liver in order to prevent liver metastasis of colorectal cancer? During early study of this study, we found that Gegen Decoction could protect the liver function, inhibit the proliferation of colorectal cancer cells, reduce the expression of ICAM-1 and the number of Treg cell in the tumor microenvironment, thus, it could reduce the degree of liver metastasis of colorectal cancer. What is the relationship between liver microenvironment and metastasis of colorectal cancer? What is the signal pathway? These questions need further study. The study on this mechanism could be a powerful evidence that the Chinese medicine theory of "preventive treatment of disease"could play a guiding role in the inhibition of tumor metastasis.

中医"治未病"理论强调"已病防变"、"瘥后防复"应"先安未受邪之地"，这是预防已患疾病复发、转变的临床指导思想。结直肠癌最容易出现肝转移，提前抑制肝转移是决定结直肠癌患者预后的关键点，也正契合"先安未受邪之地"的预防理念。肿瘤微环境的变化对肿瘤转移有着重要作用，SDF-1/CXCR4生物学轴可部分解释肿瘤脏器转移的特异性，而Toll样受体信号通路与肿瘤微环境的调控有着密切关系，但SDF-1/CXCR4轴与Toll 样受体信号通路的关系在国内外尚未见报道。前期研究表明，葛根散能改善酒精损伤小鼠的肝脏功能和肝癌小鼠的病理形态并对结直肠癌有抑制作用，能改善结直肠癌肝转移模型的肝脏微环境。由此，我们大胆假设，葛根散可能正是通过调控肝脏微环境从而达到抑制结直肠癌肝转移作用的！但是，肝脏微环境与结直肠癌之间的关系如何？其信号途径如何？探索其机制可以作为"治未病"理论在肿瘤转移方面指导作用的有力佐证。

结直肠癌发生肝脏转移是导致患者死亡的主要原因，若能发现有效的防治药物，其临床意义重大。课题组预实验发现，葛根散在抑制结直肠癌肝转移方面的效果并不是很理想，考虑到可能是由于葛根散的组成中活血化瘀药物较少，与结直肠癌肝转移的病因病机并不完全吻合，因此我们邀请国医大师刘尚义教授对葛根散的组方进行了重新调整，确定了在葛根散的基础上，增加蟾皮、威灵仙等多味中药重新炼制，并更名为蟾灵膏，作为本次研究的药物。为了更加直观、客观和动态的观察结直肠癌细胞在裸鼠结肠的生长情况，我们增加了LoVo细胞系并用荧光素酶基因对其进行了示踪标记。课题组通过4年的工作，主要完成以下研究工作：①完成蟾灵膏的急性毒理和长期毒理研究工作，证实蟾灵膏的应用安全。②明确蟾灵膏对结直肠癌CT26细胞系和结直肠癌LoVo-luc细胞系肝转移的预防和抑制作用。③揭示蟾灵膏对肝脏微环境相关免疫因子及SDF-1/CXCR4生物学轴的影响。④探讨了SDF-1/CXCR4生物学轴与Toll 样受体信号通路的关系及对结直肠癌肝转移的影响。⑤已培养5名研究生毕业。⑥发表相关学术论文28篇，其中SCI论文3篇，北大中文核心8篇，已接收待见刊SCI论文1篇。⑦申请国家发明专利2项。⑧已获得贵州省中医肿瘤传承与科技创新人才基地。