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, one of CAF origins, with ESCC cells. Periostin (POSTN) 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 extracellular signal-regulated kinase (Erk). Recombinant human POSTN activated Akt and Erk signaling pathways in ESCC cells, enhancing survival and migration. The suppression of POSTN in CAF-like cells by siRNA during direct co-culture also suppressed enhanced survival and migration in ESCC cells. In ESCC cells, knockdown of POSTN receptor integrin β4 inhibited Akt and Erk phosphorylation, and survival and migration increased by POSTN. POSTN also enhanced mesenchymal stem cell and macrophage migration and endowed macrophages with tumor-associated macrophage-like properties. Immunohistochemistry showed that high POSTN expression in the cancer stroma was significantly associated with tumor invasion depth, lymphatic and blood vessel invasion, higher pathologic stage, CAF marker expression, and infiltrating tumor-associated macrophage numbers. Moreover, patients with ESCC with high POSTN expression exhibited poor postoperative outcomes. Thus, CAF-secreted POSTN contributed to tumor microenvironment development. These results indicate that POSTN may be a novel therapeutic target for ESCC.

Miyako S ，Koma YI ，Nakanishi T ，Tsukamoto S ，Yamanaka K ，Ishihara N ，Azumi Y ，Urakami S ，Shimizu M ，Kodama T ，Nishio M ，Shigeoka M ，Kakeji Y ，Yokozaki H ... -  《-》

Urokinase plasminogen activator secreted by cancer-associated fibroblasts induces tumor progression via PI3K/AKT and ERK signaling in esophageal squamous cell carcinoma.

Tian B ，Chen X ，Zhang H ，Li X ，Wang J ，Han W ，Zhang LY ，Fu L ，Li Y ，Nie C ，Zhao Y ，Tan X ，Wang H ，Guan XY ，Hong A ... -  《Oncotarget》

Fibroblast activation protein-positive fibroblasts promote tumor progression through secretion of CCL2 and interleukin-6 in esophageal squamous cell carcinoma.

Higashino N ，Koma YI ，Hosono M ，Takase N ，Okamoto M ，Kodaira H ，Nishio M ，Shigeoka M ，Kakeji Y ，Yokozaki H ... -  《-》

Periostin derived from cancer-associated fibroblasts promotes esophageal squamous cell carcinoma progression via ADAM17 activation.

Periostin (POSTN) is a matricellular protein that was originally identified in osteoblasts. Past studies have shown that POSTN is also preferentially expressed in cancer-associated fibroblasts (CAFs) in various types of cancer. We previously demonstrated that the increased expression of POSTN in stromal tissues is associated with an unfavorable clinical outcome in esophageal squamous cell carcinoma (ESCC) patients. In this study, we aimed to elucidate the role of POSNT in ESCC progression and its underlying molecular mechanism. We found that POSTN is predominantly produced by CAFs in ESCC tissues, and that CAFs-cultured media significantly promoted the migration, invasion, proliferation, and colony formation of ESCC cell lines in a POSTN-dependent manner. In ESCC cells, POSTN increased the phosphorylation of ERK1/2 and stimulated the expression and activity of a disintegrin and metalloproteinase 17 (ADAM17), which is critically involved in tumorigenesis and tumor progression. The effects of POSTN on ESCC cells were suppressed by interfering with the binding of POSTN to integrin αvβ3 or αvβ5 using neutralizing antibody against POSTN. Taken together, our data show that CAFs-derived POSTN stimulates ADAM17 activity through activation of the integrin αvβ3 or αvβ5-ERK1/2 pathway and thereby contributes to the progression of ESCC.

Ishibashi Y ，Mochizuki S ，Horiuchi K ，Tsujimoto H ，Kouzu K ，Kishi Y ，Okada Y ，Ueno H ... -  《-》

PAI-1 derived from cancer-associated fibroblasts in esophageal squamous cell carcinoma promotes the invasion of cancer cells and the migration of macrophages.

Sakamoto H ，Koma YI ，Higashino N ，Kodama T ，Tanigawa K ，Shimizu M ，Fujikawa M ，Nishio M ，Shigeoka M ，Kakeji Y ，Yokozaki H ... -  《-》