PDF file - 34K, HD-MSC were cultured at 0.5x105 cells/cm2. After 3 days, 105 cells of NHL-B cells lines were seeded on these stromal cells and stimulated or not with 30�M celecoxib and/or 50ng/ml of TRAIL. B cell apoptosis was analyzed by flow cytometry gating on CD19posCD20posCD105neg active capsase-3pos cells. Apoptosis level of B cell lines without stromal cells (figure 2) was reported with dotted lines Mean plus-minus SD, n=2.
ARTICLE ABSTRACT
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 tumor B-cell survival and in the resistance to antitumor immune response. New therapies must consider both tumor cells and their surrounding microenvironmentExperimental 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); 2663–73. ©2014 AACR.
