Tumor-associated macrophages induce invasion and poor prognosis in human gastric cancer in a cyclooxygenase-2/MMP9-dependent manner.

Cyclooxygenase-2 (COX2) and tumor-associated macrophages (TAMs) are associated with invasion, angiogenesis, and poor prognosis in many human cancers. However, the role of TAMs in human gastric cancer (GC) remains elusive. In the present study, we first measured COX2 expression and TAM infiltration in human GC tissues using double immunohistochemical staining. Then, we indirectly cocultured M2-polarized macrophages derived from human THP-1 cells with GC cells as an in vitro model. Transwell assays, siRNA transfection, treatment with a COX2 inhibitor and Western blotting were used to investigate the relationship among TAMs, invasion and COX2 expression as well as the underlying molecular mechanism. Double IHC staining showed that TAMs were aggregated near GC tumor nests and had high COX2 expression; moreover, the number of TAMs that infiltrated the tumor nest was correlated with the depth of invasion, COX2 expression and poor prognosis in human GC. In an in vitro assay, after treatment with phorbol myristate acetate (PMA), the THP-1 cells differentiated into M2 macrophages and induced COX2/MMP9-dependent invasiveness in GC cells. Pretreatment of GC cells with COX2 siRNA or a COX2 inhibitor (Celecoxib) can negate these promoting effects. The results of this study and those of our previous studies indicate that coculture with M2-polarized macrophages can induce the COX2-dependent release of matrix metalloproteinase-9 (MMP9), which subsequently increases the invasiveness of GC cells. Our data may provide a basis for targeting TAMs or for polarizing TAMs through immune regulation to halt GC progression, which could soon become a nonsurgical treatment for human gastric cancer. AJTR