title: Role of metalloproteinases MMP-9 and MT1-MMP in CXCL12-promoted myeloma cell invasion across basement membranes.
abstract: Malignant plasma cells in multiple myeloma home to the bone marrow (BM), accumulate in different niches and, in late disease, migrate from the BM into blood. These migratory events involve cell trafficking across extracellular matrix (ECM)-rich basement membranes and interstitial tissues. Metalloproteinases (MMP) degrade ECM and facilitate tumour cell invasion. The chemokine CXCL12 is expressed in the BM, and it was previously shown that it triggers myeloma cell migration and activation. In the present work we show that CXCL12 promotes myeloma cell invasion across Matrigel-reconstituted basement membranes and type I collagen gels. MMP-9 activity was required for invasion through Matrigel towards CXCL12, whereas TIMP-1, a MMP-9 inhibitor that we found to be expressed by myeloma and BM stromal cells, impaired the invasion. In addition, we show that the membrane-bound MT1-MMP metalloproteinase is expressed by myeloma cells and contributes to CXCL12-promoted myeloma cell invasion across Matrigel. Increase in MT1-MMP expression, as well as induction of its membrane polarization by CXCL12 in myeloma cells, might represent potential mechanisms contributing to this invasion. CXCL12-promoted invasion across type I collagen involved metalloproteinases different from MT1-MMP. These data indicate that CXCL12 could contribute to myeloma cell trafficking in the BM involving MMP-9 and MT1-MMP activities.
authors.affiliation: Department of Immunology, Centro de Investigaciones Biológicas, CSIC, 28040 Madrid, Spain.
authors.forename: Marisa
authors.initials: M
authors.lastname: Parmo-Cabañas
authors.forename: Isabel
authors.initials: I
authors.lastname: Molina-Ortiz
authors.forename: Salomón
authors.initials: S
authors.lastname: Matías-Román
authors.forename: David
authors.initials: D
authors.lastname: García-Bernal
authors.forename: Xonia
authors.initials: X
authors.lastname: Carvajal-Vergara
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Valle
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
authors.forename: Alicia G
authors.initials: AG
authors.lastname: Arroyo
authors.forename: Joaquin
authors.initials: J
authors.lastname: Teixidó
mesh_terms: D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology*; D001672:Biocompatible Materials; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D003094:Collagen; D024042:Collagen Type I / Q000378:metabolism; D004338:Drug Combinations; D005109:Extracellular Matrix / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D011509:Proteoglycans; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D024042:Collagen Type I; D004338:Drug Combinations; D007797:Laminin; D009363:Neoplasm Proteins; D011509:Proteoglycans; D019715:Tissue Inhibitor of Metalloproteinase-1; C059485:matrigel; D003094:Collagen; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D020780:Matrix Metalloproteinase 9