Abstract
ObjectivesInterleukin-17A (IL-17A) is pro-inflammatory cytokine and acts as profibrotic factor in the fibrosis of various organs. Fibrosis tumor-like peritoneal dissemination of gastric cancer interferes with drug delivery and immune cell infiltration because of its high internal pressure. In this study, we examined the relationship between IL-17A and tissue fibrosis in peritoneal dissemination and elucidated the mechanism of fibrosis induced by IL-17A using human peritoneal mesothelial cells (HPMCs) and a mouse xenograft model.MethodsSeventy gastric cancer patients with peritoneal dissemination were evaluated. The correlation between IL-17A and fibrosis was examined by immunofluorescence and immunohistochemistry. A fibrosis tumor model was developed based on subcutaneous transplantation of co-cultured cells (HPMCs and human gastric cancer cell line MKN-45) into the dorsal side of nude mice. Mice were subsequently treated with or without IL-17A. We also examined the effect of IL-17A on HPMCs in vitro.ResultsThere was a significant correlation between IL-17A expression, the number of mast cell tryptase (MCT)-positive cells, and the degree of fibrosis (r = 0.417, P < 0.01). In the mouse model, IL-17A enhanced tumor progression and fibrosis. HPMCs treated with IL-17A revealed changes to a spindle-like morphology, decreased E-cadherin expression, and increased α-SMA expression through STAT3 phosphorylation. Moreover, HPMCs treated with IL-17A showed increased migration.ConclusionsIL-17A derived from mast cells contributes to tumor fibrosis in peritoneal dissemination of gastric cancer. Inhibiting degranulation of mast cells might be a promising treatment strategy to control organ fibrosis.
Highlights
Gastric cancer is one of the most common causes of cancer mortality worldwide
We previously reported that Transforming growth factor (TGF)-βmediated activation of human peritoneal mesothelial cells (HPMCs) induces an epithelial mesenchymal transition (EMT)-like process, and HPMCs activated by TGF-β drive the process of fibrosis by acting as cancer-associated fibroblasts (CAFs) [17]
We examined which cells are the major source of IL-17A and the relationship between tissue fibrosis and IL-17A in peritoneal dissemination of gastric cancer
Summary
A critical factor of poor prognosis and the most common metastatic pattern in gastric cancer is peritoneal dissemination [1,2,3]. Peritoneal dissemination is characterized by diffusely infiltrating and proliferating. A major source of IL-17A in the primary lesions of gastric cancer is mast cells, and the amount of IL-17A secreted by mast cells is correlated with poor overall survival [9]. Esophageal squamous carcinoma, and hepatocellular carcinoma, IL-17A-producing mast cells infiltrate the tumor stroma [10,11,12]. The role of IL-17A in cancer is thought to correlate with tumorigenesis, tumor proliferation, and angiogenesis [13]. A previous study reported a correlation between IL-17A and the degree of tissue fibrosis in systemic sclerosis and lung disease [15]; no study has reported a relationship between tissue fibrosis and IL-17A in cancer
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