基于肿瘤微环境中CAFs增殖及相关因子表达探讨消痰散结方抗胃癌侵袭转移的机制研究

Tumor microenvironment is closely related to the invasion and metastasis of gastric cancer. Cancer-associated fibroblasts (CAFs) are the one of the most important stromal cells mediating tumor-stroma cross-talk. It can directly act on malignant cells in a direct cell-to-cell way and by secreting diverse soluble cytokines, such as SDF-1α, regulating tumor evolution, growth, angiogenesis, immunity and aggressive behaviors (invasion and metastasis).We have focused on the study of the prevention and treatment of gastric cancer for many years. Our professor Wei-Pinkang has established the theory of “dispersing phlegm and disspating bind” for treating patients. “Phlegm turbidity” is the environment basis of gastric cancer occurrence and development. The therapeutic effect is satisfactory, which is one of effective methods for the treatment of gastric cancer. Our previous study found that Xiaotan Sanjie decoction not only inhibits the invasion and metastasis of gastric cancer, but also down-regulate the expression of FAP in orthotopic-transplanted nude mice, regulating the expression of inflammation factor in tumor tissue. Does Xiaotan Sanjie decotion inhibitie gastric cancer invasion and metastasis by influencing the CAFs？ The purpose of this study is to discover the role and mechanism of Xiaotan Sanjie decoction on Gastric Cancer Cell migration and invasion based on CAFs proliferation and related factor expression in tumor microenvironment from protein, genetic and molecular level, in vitro and vivo experiments. The study is to provide data support for the theory of “Qinghua phlegm turbidity” scientific connotation on inhibition of gastric cancer invasion and metastasis.

肿瘤微环境与胃癌的侵袭转移密切相关。肿瘤成纤维细胞(CAFs)是肿瘤微环境中最多的基质细胞，活化的CAFs通过与肿瘤细胞相互作用或分泌多种因子如趋化因子SDF-1α在胃癌的侵袭转移中发挥重要作用。本学科在长期胃癌防治实践中，提出痰浊内蕴是胃癌发生、发展的环境基础，创制消痰散结方用于胃癌的复发与转移，临床疗效明确，是治疗胃癌的有效方法之一。课题组前期研究发现，消痰散结方不仅可抑制胃癌的侵袭转移，而且能下调成纤维细胞的活化状态，调节肿瘤组织中炎性因子的表达。那么：消痰散结方是否通过影响CAFs而发挥其抗胃癌侵袭转移的作用呢？本课题拟通过动物和细胞学实验，观察消痰散结方对CAFs的增殖及其相关分泌因子表达的影响，重点从SDF-1α角度，从蛋白、基因分子水平探讨该方是否通过干预CAFs而发挥抗胃癌侵袭转移的作用，为阐释中医清化“痰浊”抑制胃癌侵袭转移的科学内涵提供数据支持。

肿瘤微环境与胃癌的侵袭转移密切相关。肿瘤成纤维细胞(CAFs)是肿瘤微环境中最多的基质细胞，活化的CAFs通过与肿瘤细胞相互作用或分泌多种因子如趋化因子SDF-1α在胃癌的侵袭转移中发挥重要作用。本学科在长期胃癌防治实践中，提出痰浊内蕴是胃癌发生、发展的环境基础，创制消痰散结方用于胃癌的复发与转移，临床疗效明确，是治疗胃癌的有效方法之一。课题组前期研究发现，消痰散结方不仅可抑制胃癌的侵袭转移，而且能下调成纤维细胞的活化状态，调节肿瘤组织中炎性因子的表达。.故本课题在前期研究基础上，以CAFs为研究靶点，模拟肿瘤微环境，拟通过动物和细胞学实验，观察消痰散结方对CAFs增殖及其相关分泌因子的影响，并重点从SDF-1α/CXCR4轴角度，探讨该方通过干预CAFs发挥抗胃癌侵袭转移的可能机制。研究结果显示，我们发现消痰散结方可以干预CAFs的增殖，及CAFs分泌的相关炎症因子IL-1β、IL-6、VEGF及SDF-1α的表达，其中对SDF-α影响较为明显，与MKN45共培养，可以发挥抑制胃癌细胞迁移和侵袭能力，SDF-1α-CXCR4的通路可能是其主要参与通路。我们课题组多年临床中认为痰浊内蕴是胃癌发生、发展的物质基础，采用的“消痰散结方”为主要治则，贯穿治疗始终，意在清除胃癌痰浊环境，从根本上消除胃癌细胞赖以存在和发展的物质基础。通过本实验，我们证实了消痰散结方可以通过抑制CAFs的增殖起到抑制胃癌细胞侵袭和转移的效果，CAFs可能是其作用的一个靶点，为阐释中医清化“痰浊”抑制胃癌侵袭转移的科学内涵提供数据支持。