A C-X-C chemokine receptor type 2-dominated crosstalk between tumor cells and macrophages drives gastric cancer metastasis

Purpose: C-X-C chemokine receptor type 2 (CXCR2) is a key regulator that drives immune suppression and inflammation in tumor microenvironment. CXCR2-targeted therapy has shown promising results in several solid tumors. However, the underlying mechanism of CXCR2-mediated crosstalk between gastric cancer (GC) cells and macrophages still remains unclear. Experimental Design: The expression of CXCR2 and its ligands in 155 human GC tissues was analyzed via immunohistochemistry, and the correlations with clinical characteristics were evaluated. A co-culture system was established, and functional assays, including ELISA, transwell, MTT, and qPCR, were performed to determine the role of the CXCR2 signaling axis in promoting GC growth and metastasis. A xenograft GC model and a lymph node metastasis model were established to study the function of CXCR2 in vivo. Results: CXCR2 expression is associated with prognosis of GC patients (P=0.002). Of all the CXCR2 ligands, CXCL1 and CXCL5 can significantly promote migration of GC cells. Macrophages are the major sources of CXCL1 and CXCL5 in the GC microenvironment, and promote migration of GC cells through activating a CXCR2/STAT3 feed-forward loop. GC cells secrete TNF-α to induce release of CXCL1 and CXCL5 from macrophages. Inhibiting CXCR2 pathway of GC cells can suppress migration and metastasis of GC in vitro and in vivo. Conclusion: Our study suggested a previously uncharacterized mechanism through which GC cells interact with macrophages to promote tumor growth and metastasis, suggesting that CXCR2 may serve as a promising therapeutic target to treat GC.

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