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 investigated the involvement of interstitial collagenase (MMP-1) and gelatinases (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 not subjected to regulation either by interleukin-6 (IL-6), the major myeloma cell growth factor, or by other cytokines involved in the multiple myeloma cytokine network. In the tumoral environment, we show that bone marrow stromal cells express MMP-1 and MMP-2. Whereas MMP-1 is positively regulated by IL-1beta, tumor necrosis factor-alpha, and Oncostatin M, MMP-2 is not modulated by any of these cytokines. To evaluate whether myeloma cells can modify the bone marrow stromal environment, 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 activities could represent a new therapeutical approach in multiple myeloma.
Barillé
S
S
INSERM U463, Oncogénèse Immunohématologique, Institut de Biologie, Nantes, France.
Akhoundi
C
C
Collette
M
M
Mellerin
M P
MP
Rapp
M J
MJ
Harousseau
J L
JL
Bataille
R
R
Amiot
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002117:Calcitriol / Q000494:pharmacology; D018920:Coculture Techniques; D017364:Collagenases / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D004790:Enzyme Induction; D004792:Enzyme Precursors / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism*; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism*; D009101:Multiple Myeloma / Q000201:enzymology*; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D004792:Enzyme Precursors; D006131:Growth Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; C508351:OSM protein, human; D010455:Peptides; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D053683:Oncostatin M; D016753:Interleukin-10; D003907:Dexamethasone; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; D002117:Calcitriol