METALLOPROTEINASES IN MULTIPLE-MYELOMA - PRODUCTION OF MATRIX METALLOPROTEINASE-9 (MMP-9), ACTIVATION OF PROMMP-2, AND INDUCTION OF MMP-1 BY MYELOMA CELLS

Multiple myeloma is a very devastating cancer with a high capacity to destroy bone matrix. Matrix metalloproteinases (MMPs) play a critical role in bone remodeling and tumor invasion, In this study, we have inv estigated the involvement of interstitial collagenase (MMP-1) and gela tinases (MMP-2 and MMP-9) in the biology of multiple myeloma. We show (1) that myeloma cells express MMP-9 and (2) that this expression is n ot subjected to regulation either by interleukin-6 (IL-B), the major m yeloma cell growth factor, or by other cytokines involved in the multi ple myeloma cytokine network. In the tumoral environment, we show that bone marrow stromal cells express MMP-1 and MMP-2. Whereas MMP-1 is p ositively regulated by IL-1 beta, tumor necrosis factor-alpha, and Onc ostatin M, MMP-2 is not modulated by any of these cytokines. To evalua te whether myeloma cells can modify the bone marrow stromal environmen t, we have examined these MMP activities in coculture. Interestingly, we have observed an upregulation of MMP-1 and a partial conversion of the proMMP-2 into its activated form. We conclude that the increase of MMP activity produced or induced by myeloma cells in these cocultures could favor bone resorption and tumor invasion. Inhibition of such ac tivities could represent a new therapeutical approach in multiple myel oma, (C) 1997 by The American Society of Hematology.