从肿瘤微环境角度探讨胰腺癌不同中医证型的分子基础研究

ZHENG, also known as syndrome, is the essence of traditional Chinese medicine (TCM) theory and clinical treatment. ZHENG study has been remaining one the most important research topics in TCM, including TCM for cancer. It has been confirmed that tumor cells do not act in isolation, but rather subsist in a rich microenvironment provided by resident stromal cells. It may be realized that cancer progress is mainfested with different ZHENG macroscopically, while it is shown microscopically as alteration of tumor cells and their surrounding microenvironment and the internal environmtnt of the body. Therefore, ZHENG study in pancreatic cancer from the perspective of tumor microenvironment and body internal environment is in line with the holistic view of TCM theory. In addition, we have previously suggested an involvement between ZHENG and the tumor microenvironment in pancreatic cancer. Therefore, in this study we will establish mouse xenograft pancreatic cancer models with different TCM ZHENG to study the correlation between ZHENG and tumor microenvironment in pancreatic cancer.We will also evaluated the correlation between herbal medicine-induced alteration of tumor microenvironment under different ZHENG conditions and treatment response. Based on which, combined with ZHENG evaluation in pancreatic cancer patients, we try to unveil the molecular basis of TCM ZHENG in pancreatic cancer.

证是中医学理论和临床治疗的核心，针对证实质研究一直是中医研究包括中医肿瘤研究的重要内容。恶性肿瘤发生发展的过程，目前被认为是肿瘤细胞与其微环境相互作用的过程，而该过程宏观上可表现为中医证候，其微观和客观层面则可表现为肿瘤细胞及其所处的微环境变化、以及该微环境变化所引起的机体内环境变化。因此从肿瘤微环境以及机体内环境来进行胰腺癌中医证型实质研究，符合中医"整体观"的诊治原则。而且，我们前期研究也提示，胰腺癌不同中医证型可能存在肿瘤微环境的差异。所以，本研究拟通过胰腺癌不同中医"证"动物模型，结合胰腺癌患者中医证型研究，明确胰腺癌不同中医证型与肿瘤微环境之间可能存在的相关性，并通过不同治则中药干预研究，以期明确胰腺癌不同中医证型下肿瘤微环境变化、及其与中药治疗敏感性的关联，从而揭示胰腺癌中医证型的分子基础。

我们前期研究提示，胰腺癌不同中医证型间存在肿瘤微环境的差异。本研究建立不同中医证型小鼠模型。观察胰腺肿瘤组织肿瘤微环境细胞及相关细胞因子变化，结果发现不同中医证型肿瘤瘤体的体积存在差异，证型和肿瘤微环境中的CAF和TAM密切相关，证型组中细胞因子的表达水平低于对照组，其中以湿热组较为明显，血瘀组与对照组之间的差异较小。在进一步“方证相应”探讨胰腺癌不同证型分子基础的研究中发现不同中医证型小鼠在接受对应中药方剂治疗后，瘤体体积并未出现明显变化，主要来源于CAF和TAM的细胞因子SDF-1、CXCR4、CCL-5、CCR5在各组中的表达未见明显差异。在临床研究中，我们发现胰腺癌患者外周血微环境中的细胞因子可以用于患者的治疗决策并预测胰腺癌的预后。较高的白细胞数、中性粒细胞数、单核细胞数、NLR值、PLR值、纤维蛋白原和较低的LMR值与降低的生存期显著相关。这些因子是胰腺癌患者独立的生存期预测指标，提示了晚期胰腺癌患者的不良预后。同时我们也发现系统性炎症反应与中医证型之间存在相关性，不同中医证型之间存在显著差异。以湿热证组患者的炎症反应最低，脾虚证组患者炎症反应最高。