Tumor microenvironment in diffuse large B-cell lymphoma: Matrixmetalloproteinases activation is mediated by osteopontin overexpression

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with variable patterns of behavior and responses to therapy. NHL development and invasion depend onmultiple interactions between tumor cells and non-neoplastic cells. Such interactions are usually modulated by several cytokines. Accordingly, it was demonstrated that matrix-metalloproteinase (MMP)-2 and MMP-9 were activated in human lymphoid cell lines by interleukin-6 (IL-6). The activation of these enzymes is associated with tumor invasion andmetastasis in human cancers. MMPs are also activated in several cancers by osteopontin (OPN), a secreted glycoprotein that regulates cell adhesion, migration, and survival. However, it is still unclear if MMPs play a role in NHL development and if their activation is determined by OPN and/or IL-6. In the present study, two groups of 78 NHL patients and 95 healthy donors were recruited for the analysis of OPN, MMP-2, MMP-9 and IL-6. Significant higher circulating levels ofMMP-2,MMP-9, OPN and IL-6 were observed in NHL patients when compared to healthy donors. Similar data were obtained by analyzing the activity of both MMP-2 and MMP-9. The multivariate regression model indicates that, in both NHL cases and healthy donors, OPN is associated with the increase of MMP-2 and MMP-9 levels independently of IL-6. These data were first confirmed by "in silico" analyses and then by "in vitro" experiments conducted on peripheral blood mononuclear cells randomly selected from both NHL patients and healthy donors. Overall, our data suggest that the activation ofMMPs in NHL development ismostly associated with OPN. However, IL-6 may play an important role in the lymphomagenesis through the activation of other molecular pathways.