Bone marrow endothelial cells increase the invasiveness of human multiple myeloma cells through upregulation of MMP-9: evidence for a role of hepatocyte growth factor

• Published in: Leukemia Vol. 18; no. 5; pp. 976 - 982
• Main Authors: VANDE BROEK, I, ASOSINGH, K, ALLEGAERT, V, LELEU, X, FACON, T, VANDERKERKEN, K, VAN CAMP, B, VAN RIET, I
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01.05.2004; Nature Publishing Group
• Subjects: Angiogenesis; Antibodies; Basements; Biological and medical sciences; Blood vessels; Bone marrow; Bone Marrow Cells - physiology; Cells; Cells, Cultured; Cytokines; Endothelial cells; Endothelial Cells - physiology; Endothelium; Gelatinase B; Growth factors; Hematologic and hematopoietic diseases; Hematology; Hepatocyte growth factor; Hepatocyte Growth Factor - physiology; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunology; Immunopathology; Invasiveness; Kinases; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes; Matrix metalloproteinase; Matrix Metalloproteinase 9 - physiology; Matrix metalloproteinases; Medical sciences; Membranes; Metalloproteinase; Multiple myeloma; Multiple Myeloma - enzymology; Multiple Myeloma - pathology; Neoplasm Invasiveness; Pathogenesis; Stimulation; Up-Regulation; Belgium; Human; Immunopathology; Endothelial cell; multiple myeloma; Hematology; Enzyme; Hepatocyte growth factor; Metalloendopeptidases; transendothelial invasion; Malignant hemopathy; Myeloma; Gelatinase B; Invasion; Endothelium; Peptidases; Immunoglobulinopathy; Lymphoproliferative syndrome; Bone marrow; Hydrolases; Homing phenomenon; homing; MMP-9
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2403331

The migration of multiple myeloma (MM) cells from the circulation into the bone marrow (BM) implicates that they must have the capacity to cross the BM endothelium including the subendothelial basement membrane. In this study, human CD138+ MM cells were immunomagnetically isolated from BM samples of MM patients and their invasion through Matrigel, that is, a reconstituted basement membrane, was determined. We demonstrated that primary MM cells have the capacity to transmigrate through basement membrane and that this invasiveness was considerably increased when assessed on Matrigel filters coated with BM endothelial cells (EC) (4LHBMEC line) (transendothelial invasion). The isolated MM cells were shown by zymography to secrete matrix metalloproteinase (MMP)-9 and anti-MMP-9 antibodies inhibited transendothelial invasion, indicating that MMP-9 is involved in this process. BM EC were found to increase the MMP-9 secretion in MM cells, indicating that EC enhance MM cell invasion through stimulation of MMP-9 secretion. BM EC were found to produce hepatocyte growth factor (HGF), and this cytokine also stimulated MMP-9 secretion in MM cells, while anti-HGF antibodies significantly inhibited EC-stimulated MM cell invasion. In summary, our findings provide evidence that MM cell-BM EC interactions enhance the invasion of human MM cells through stimulation of MMP-9 secretion.