Association of enhanced epithelial-mesenchymal transition signature with tumor microenvironment, angiogenesis, and survival in gastric cancer.

Abstract

e16002 Background: Among the hallmarks of cancer, epithelial-mesenchymal transition (EMT) that epithelial cancer cells gain the characteristics of mesenchymal cells, is one of the key mechanisms of cancer cell metastasis. On the other hand, the clinical relevance of EMT that occurs in gastric cancer patients has not been clearly shown. Methods: To measure the level of EMT in gastric cancer, gene set variation analysis was used to score total of 807 gastric cancer patient samples from two independent large cohorts; TCGA and GSE84437. Results: EMT high gastric cancer was significantly associated with worse overall survival (hazard ratio (HR)=1.74, p=0.011 in the TCGA, and HR=2.01, p<0.001 in the GSE84437), and the association was stronger with EMT signature score compared to expressions of each EMT-related genes, CDH1, CDH2, VIM, or FN1. EMT signature levels were not significantly different among gastric cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, and pancreatic ductal adenocarcinoma, and high level of EMT signature was associated with survival only in gastric cancer. Among the histological types, mucinous and diffuse type had high EMT level compared to tubular, papillary, or signet gastric cancer ( p<0.001). EMT signature level was significantly correlated with tumor depth and AJCC stage (all p<0.001), but not consistently with lymphatic metastasis. Interestingly, the EMT score was independent factor for patient survival including clinicopathological features, not only for overall survival but also disease-specific survival in the TCGA cohort (multivariate; p=0.006 and 0.032, respectively). EMT high gastric cancer was associated with low fraction of Th1 cells and high fraction of dendritic cells and M1 macrophages (all p<0.001 in both cohort), but not with interferon-gamma immune response. EMT high gastric cancer tended to be inversely correlated with cell proliferation-related gene sets, and significantly associated with high infiltration fraction of stromal cells, including fibroblasts, adipocytes (all p<0.001). On the other hand, they significantly enriched multiple pro-cancerous gene sets, such as TGF-β signaling, hypoxia, and angiogenesis, consistent with infiltration of angiogenesis-related stromal cells such as microvascular and lymphatic endothelial cells, and pericytes (all p<0.001). These results were shown consistently in two large cohort; TCGA and GSE84437. Conclusions: EMT signature in a bulk tumor was associated with cancer aggravating pathways such as TGF-β signaling, hypoxia, and angiogenesis, as well as with worse survival in gastric cancer patients.