Novel treatment strategy targeting interleukin-6 induced by cancer-associated fibroblast for peritoneal metastasis of gastric cancer

Abstract Cancer-associated fibroblasts (CAFs) are one of the crucial components in the tumor microenvironment (TME) of the peritoneal metastasis (PM) and contribute to tumor progression and metastasis via the secretion of interleukin-6 (IL-6). Herein, we have investigated the role of IL-6 in PM of gastric cancer (GC) and whether anti-IL-6 receptor antibody (anti-IL-6R Ab) could inhibit PM of GC. IL-6 and α-smooth muscle (α-SMA) expressions were immunohisitochemically investigated in clinical samples of GC and PM. And we investigated the interactions between CAFs and GC cells in vitro. Moreover, anti-tumor effects of anti-IL-6R Ab to PM of GC were investigated in murine orthotopic 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. And higher IL-6 and α-SMA expressions were also observed with PM of GC. In vitro, the differentiation of fibroblasts into CAFs and chemoresistance was observed in GC cells cocultured with fibroblasts. Anti-IL-6R Ab inhibited the progression of PM of GC cells cocultured with fibroblasts in orthotopic mouse model although it could not inhibit the progression of PM consisting of GC cells alone. IL-6 expression in TME was associated with poor prognosis of GC and CAFs were associated with establishment and progression of PM via IL-6. The anti-IL-6R Ab could inhibit PM of GC by the blockade of IL-6 secreted by CAFs, which might be a novel therapeutic strategy for PM of GC.