Abstract
Cancer-associated fibroblasts (CAFs) play important roles in cancer progression. Twist1 was recently reported to be a key regulator of CAFs in gastric cancer, but its role in other types of cancer remains unclear, especially for esophageal squamous cell carcinoma (ESCC). We assessed the Twist1 expression on stromal fibroblasts using immunohistochemistry in 169 tissue specimens from ESCC patients, and performed in vitro and in vivo experiments to confirm the role of Twist1 in CAFs of ESCC. And we investigated the biological pathways that are activated in Twist1-high ESCC using The Cancer Genome Atlas (TCGA) data. The expression of Twist1 in stromal fibroblasts was observed in 89.9% of ESCC patients and positively associated with the increased depth of tumor invasion, lymph node metastasis, and advanced clinical stage, and a significant adverse prognostic factor in overall survival. Twist1-expressing stromal fibroblasts also expressed representative CAF markers, and co-localization of Twist1 and CAF markers were confirmed by confocal immunofluorescence imaging. Bioinformatic analysis of mRNA expression data of esophageal cancer from TCGA revealed that gene sets of CAFs were highly enriched in Twist1-high ESCC. Depletion of Twist1 in ex vivo cultured ESCC CAFs induced significant decrease in migration, invasion, colony formation, sphere formation, and contractibility of ESCC cancer cells compared to control CAFs. Furthermore, Twist1-expressing fibroblasts remarkably enhanced the in vivo tumorigenicity of ESCC in a xenograft model. In conclusion, Twist1 could be a novel CAF marker for the prognostic evaluation of ESCC patients as well as a potent therapeutic target for ESCC.
Highlights
Activated fibroblasts that are recruited into cancer tissue, called cancer-associated fibroblasts (CAFs), promote tumor progression via a variety of methods, including secreting cytokines and remodeling of extracellular matrix [1]
Twist1 expression rates in stromal fibroblasts were significantly higher in esophageal squamous cell carcinoma (ESCC) (152/169, 89.9%) than in adjacent non-tumor esophageal epithelial stroma (8/20, 40.0%) (χ2 = 34.338, P < 0.001)
Twist1 expression was more frequently identified in ESCC stromal fibroblasts (89.9%) than in cancer cells (33.7%) (χ2 = 113.143, P < 0.001)
Summary
Activated fibroblasts that are recruited into cancer tissue, called cancer-associated fibroblasts (CAFs), promote tumor progression via a variety of methods, including secreting cytokines and remodeling of extracellular matrix [1]. CAFs are often characterized by the expression of platelet-derived growth factor α (PDGFRα), PDGFRβ, smooth muscle actin (SMA), fibroblast activation protein (FAP) and fibroblast-stimulating protein-1 (FSP1) in ESCC. These markers are typically expressed only in a fraction of fibroblasts within the tumor, and are not specific to CAFs [4]. We showed that Twist expression on cancer cells induces the EMT and plays a critical role in ESCC metastasis and poor outcome [6]. Associations between Twist and other CAF markers and their clinical significance remain almost completely unknown
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