Macrophage Infiltration Induces Gastric Cancer Invasiveness by Activating the β-Catenin Pathway

Background Despite evidence that activated macrophages act in an inflammatory microenvironment to promote gastric tumorigenesis via beta-catenin signaling, the effects of beta-catenin signaling on gastric cancer cell metastasis and the relationship of these cells with surrounding tumor associated macrophages have not been directly studied. Methods Immunohistochemical staining was employed to analyze 103 patients. An invasion assay was used to evaluate the relationship between macrophages and gastric cancer cells. beta-catenin gain-of-function and loss-of-function approaches were performed. To assess the beta-catenin regulation mechanism in gastric cancer cells, Western blotting and reverse-transcription polymerase chain reaction were used. Results Increased density of macrophages was associated with advanced stage and poor survival. Gastric cancer cell lines co-cultured with macrophages conditioned medium showed increased nuclear accumulation of beta-catenin and increased invading ability. AKT but not ERK regulated beta-catenin translocation. MMP7 and CD44, both beta-catenin downstream genes, were involved in macrophage-activated gastric cancer cell invasion. Conclusion(s) Collectively, the clinical data suggest that macrophage infiltration is correlated with increased grade and poor prognosis for gastric cancer patients who underwent radical resection. Macrophages may induce invasiveness by activating the beta-catenin pathway.