OPN/MMP-9 Pathway Activation in B-Cell Non-Hodgkin Lymphoma

Non-Hodgkin`s lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with variable patterns of behaviour and responses to therapy. NHL development and invasion depend on multiple interactions between tumor cells and non-neoplastic cells. Such interactions are usually modulated by several cytokines. Accordingly, it was demonstrated that in human lymphoid cell lines interleukin-6 (IL-6) activates matrix-metalloproteinase (MMP)-2 and MMP-9. The activation of these enzymes is associated with tumor invasion and metastasis 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 using both experimental and bioinformatics approaches.

Compared to healthy donors, NHL cases reported significantly higher concentrations of MMP-2 (median: 1041 ng/mL and 659 ng/mL in NHL cases and controls, respectively; p<0.01), MMP-9 (median: 114.0 ng/mL and 17.1 ng/mL; p<0.01), OPN (median: 147.0 ng/mL and 27.3 ng/mL; p<0.01), and IL-6 (median: 12.5 ng/mL and 1.7 ng/mL; p<0.01). 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. Similar data were obtained by analysing Hummel and Rosenwald datasets.

These data suggest that the activation of MMPs in NHL development is mediated by OPN and not by IL-6. However, IL-6 may play an important role in the lymphomagenesis through the activation of other molecular pathways.