Ccr-13-2305 2663..2673

Purpose:Despite therapeutic advances, non–Hodgkin lymphomas (NHL) remain incurable. They form a group of neoplasms strongly dependent on their inflammatory microenvironment, which plays an important supportive role in tumorB-cell survival and in the resistance to antitumor immune response.New therapies must consider both tumor cells and their surrounding microenvironment Experimental Design: Stromal cells, derived from bone marrow or lymph nodes, and B cells from follicular lymphoma patients were cocultured or cultured alone with celecoxib treatment, a nonsteroidal anti-inflammatory drug, and/or TRAIL, a promising cytotoxic molecule for cancer therapy. Results: In this study, we show that follicular lymphoma stromal cells produce large amounts of PGE2. This production is abrogated after celecoxib treatment, targeting the COX-2 isoenzyme involved in PGE2 synthesis. Furthermore, we demonstrate that celecoxib increases apoptosis in NHL B-cell lines and in primary follicular lymphoma B cells cocultured with stromal cells, but independently of the PGE2/COX-2 axis. Finally, celecoxib increases the apoptotic activity of TRAIL. We provide evidence that celecoxib affects proliferation and sensitizes NHL B-cell lines to apoptosis through COX-2–independent effects by slowing down the cell cycle and decreasing the expression of survival proteins, such as Mcl-1. Conclusions: These data suggest new potent strategies for NHL therapy combining drugs targeting both tumor B cells and survival signals provided by the tumor microenvironment. Clin Cancer Res; 20(10);