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Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer
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Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer
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Journal Article
Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer
2025
Overview
Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment (TME) of peritoneal metastasis (PM), where they contribute to tumor progression and metastasis via secretion of interleukin-6 (IL-6). Here, we investigated the role of IL-6 in PM of gastric cancer (GC) and assessed whether anti-IL-6 receptor antibody (anti-IL-6R Ab) could inhibit PM of GC. We conducted immunohistochemical analysis of IL-6 and α-smooth muscle (α-SMA) expressions in clinical samples of GC and PM, and investigated the interactions between CAFs and GC cells in vitro. Anti-tumor effects of anti-IL-6R Ab on PM of GC were investigated in an orthotopic murine PM model. IL-6 expression was significantly correlated with α-SMA expression in clinical samples of GC, and higher IL-6 expression in the primary tumor was associated with poor prognosis of GC. Higher IL-6 and α-SMA expressions were also observed in PM of GC. In vitro, differentiation of fibroblasts into CAFs and chemoresistance were observed in GC cells cocultured with fibroblasts. Anti-IL-6R Ab inhibited the progression of PM in GC cells cocultured with fibroblasts in the orthotopic mouse model but could not inhibit the progression of PM consisting of GC cells alone. IL-6 expression in the TME was associated with poor prognosis of GC, and CAFs were associated with establishment and progression of PM via IL-6. Anti-IL-6R Ab could inhibit PM of GC by the blockade of IL-6 secreted by CAFs, which suggests its therapeutic potential for PM of GC.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Animals
/ Cancer
/ Cancer-associated fibroblasts
/ Cancer-Associated Fibroblasts - drug effects
/ Cancer-Associated Fibroblasts - metabolism
/ Cancer-Associated Fibroblasts - pathology
/ Female
/ Humanities and Social Sciences
/ Humans
/ Interleukin-6 - antagonists & inhibitors
/ Interleukin-6 receptor antibody
/ Male
/ Mice
/ Peritoneal Neoplasms - drug therapy
/ Peritoneal Neoplasms - metabolism
/ Peritoneal Neoplasms - secondary
/ Receptors, Interleukin-6 - antagonists & inhibitors
/ Receptors, Interleukin-6 - immunology
/ Receptors, Interleukin-6 - metabolism
/ Science
/ Stomach Neoplasms - drug therapy
/ Stomach Neoplasms - metabolism
/ Stomach Neoplasms - pathology
/ Tumor Microenvironment - drug effects
/ Tumors
