ESM1 Interacts with c-Met to Promote Gastric Cancer Peritoneal Metastasis by Inducing Angiogenesis

Simple Summary Peritoneum is the most common metastasis site of gastric cancer, and angiogenesis plays a key role in peritoneal metastasis which the specific mechanism of is unknown. We focused on the peritoneal metastasis-associated secretory protein ESM1 based on the previous RNA-seq. The expression of ESM1 is up-regulated in gastric cancer tissues, and even higher in primary gastric cancer with peritoneal metastasis. Moreover, the high expression of ESM1 is significantly associated with poor prognosis. Through clinicopathological data analysis, it was found that ESM1 was positively correlated with vascular invasion. The conditioned medium of gastric cancer cells overexpressing ESM1 promoted tube formation in vitro and gastric cancer cells overexpressing ESM1 induced angiogenesis in vitro. Mechanically, ESM1 binds to c-Met receptor on the surface of endothelial cells, activates the downstream MAPK/ERK signaling pathway, and promotes the transcription and translation of pro-angiogenic molecules (such as HIF1 alpha, VEGFA and MMP9) in endothelial cell, thereby promoting peritoneal metastasis of gastric cancer. Our study may provide a new direction for the diagnosis and treatment of peritoneal metastasis of gastric cancer.Abstract The peritoneum is the most common metastatic site of advanced gastric cancer and is associated with extremely poor prognosis. Endothelial-specific molecule 1 (ESM1) was found to be significantly associated with gastric cancer peritoneal metastasis (GCPM); however, the biological functions and molecular mechanisms of ESM1 in regulating GCPM remain unclear. Herein, we demonstrated that ESM1 expression was significantly upregulated in gastric cancer tissues and positively correlated with platelet endothelial cell adhesion molecule-1 (CD31) levels. Moreover, clinical validation, in in vitro and in vivo experiments, confirmed that ESM1 promoted gastric cancer angiogenesis, eventually promoting gastric cancer peritoneal metastasis. Mechanistically, ESM1 promoted tumor angiogenesis by binding to c-Met on the vascular endothelial cell membrane. In addition, our results confirmed that ESM1 upregulated VEGFA, HIF1 alpha, and MMP9 expression and induced angiogenesis by activating the MAPK/ERK pathway. In conclusion, our findings identified the role of ESM1 in gastric cancer angiogenesis and GCPM, thus providing insights into the diagnosis and treatment of advanced gastric cancer.