肝转移是胃癌最常见的远处脏器转移，预后极差。肿瘤微环境（TME）中间质细胞与肿瘤细胞“共进化”的动态过程被认为是胃癌肝转移发生、发展的重要机制。申请人前期研究发现：1）肿瘤相关成纤维细胞（CAFs）是影响胃癌肝转移的重要间质细胞；2）赖氨酰氧化酶（LOX）作为CAFs关键分泌蛋白参与了TME“共进化”；3）TGF-β1阳性肿瘤细胞激活的CAFs是TME中LOX的主要来源；4）LOX通过影响肿瘤有氧糖酵解Warburg效应促进胃癌进展。据此，提出科学假说：CAFs信使蛋白LOX与肿瘤细胞分泌蛋白TGF-β1交互协同，通过增强TME中Warburg 效应，实现CAFs与肿瘤细胞共进化，促进胃癌肝转移。本项目拟通过体外细胞分子实验、动物模型验证、调控机制探索三个层面开展后续研究，为丰富胃癌肝转移的发病机制、完善肿瘤微环境共进化调控机理提供新的理论依据，以期为胃癌肝转移的治疗提供新的靶点和思路。

Liver metastasis is the most common distant metastasis of gastric carcinoma, and the prognosis is extremely poor. The dynamic process of "co-evolution" between stromal cells and tumor cells in the tumor microenvironment (TME) is considered to be an important mechanism for the occurrence and development of gastric carcinoma with liver metastasis. Our previous research showed that: 1) cancer associated fibroblasts (CAFs) are important stromal cells that derive liver metastasis of gastric carcinoma; 2) lysyloxidase (LOX) participates in TME "co-evolution" as a key secretory protein of CAFs; 3) CAFs activated by TGF-β1 positive cancer cells are the main source of LOX in TME; 4) LOX promotes gastric cancer progression by affecting the cancer aerobic glycolysis Warburg effect. Based on these data, the scientific hypothesis is proposed: the interaction between CAFs messenger protein LOX and cancer cell secretory protein TGF-β1, achieves the co-evolution of CAFs and cancer cells, and promotes liver metastasis of gastric carcinoma, in the way of enhancing the Warburg effect in TME. This project intends to carry out follow-up research through in vitro cell molecular experiments, animal model validation, and exploration of regulatory mechanisms to provide a new theoretical basis for enriching the pathogenesis of gastric carcinoma with liver metastasis and improving the co-evolving regulation mechanism of tumor microenvironment, in order to provide the treatment of metastasis with new targets and ideas.