Periostin in Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression by Enhancing Cancer and Stromal Cell Migration

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are involved in the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). CAF-like cells were generated through direct co-culture of human bone marrow-derived mesenchymal stem cells (MSCs), one of CAF origins, with ESCC cells, and periostin was found to be highly expressed in CAF-like cells. After direct co-culture, ESCC cells showed increased malignant phenotypes such as survival, growth, and migration, as well as increased phosphorylation of Akt and Erk. Recombinant human periostin activated Akt and Erk signaling pathways in ESCC cells, enhancing survival and migration. The suppression of periostin in CAF-like cells by small interfering RNA during direct co-culture also suppressed enhanced survival and migration in ESCC cells. In ESCC cells, knockdown of periostin receptor integrin β4 inhibited Akt and Erk phosphorylation, as well as survival and migration increased by periostin. Periostin also enhanced MSC and macrophage migration and endowed macrophages with tumor-associated macrophage (TAM)-like properties. Immunohistochemistry showed that high periostin expression in the cancer stroma was significantly associated with tumor invasion depth, lymphatic and blood vessel invasion, higher pathological stage, CAF marker expression, and infiltrating TAM numbers. Moreover, patients with ESCC with high periostin expression exhibited poor postoperative outcomes. Thus, CAF-secreted periostin contributed to tumor microenvironment development. These results indicate that periostin may be a novel therapeutic target for ESCC.