title: Transendothelial migration of myeloma cells is increased by tumor necrosis factor (TNF)-alpha via TNF receptor 2 and autocrine up-regulation of MCP-1.
abstract: The proinflammatory cytokine tumor necrosis factor (TNF)-alpha has been shown to facilitate leukocyte transendothelial migration. In multiple myeloma, TNF-alpha is an important factor in the promotion of growth and survival of the malignant cells. Studies have shown that enhanced TNF-alpha levels in myeloma patients correlated with aggressive disease. Therefore, we investigated the effect of recombinant human TNF-alpha on the migrational behavior of myeloma cells across the physiological barrier of the major disease compartment, i.e., human bone marrow endothelial cells. In the presence of TNF-alpha, we observed significantly increased migration both in established myeloma cell lines and in plasma cells from myeloma patients. Expression of TNF-receptor 2 (TNF-R2) but not TNF-receptor 1 (TNF-R1) was detected in myeloma cell lines. Myeloma cells of patients also showed expression of TNF-R2 but not TNF-R1. The effect of TNF-alpha could not be explained by altered expression of adhesion molecules or metalloproteases. Instead, we found an up-regulation of monocyte chemoattractant protein (MCP)-1 and confirmed that myeloma cells express the relevant receptor C-C chemokine receptor 2. Preincubation of myeloma cells with recombinant human MCP-1 also enhanced cell migration, and this effect, as well as the effect of TNF-alpha, was abolished by treatment with anti-MCP-1 antibody. In contrast, migration of myeloma cells in the direction of an MCP-1 gradient, i.e., chemotaxis, could not be observed in the cell lines investigated. Additionally, the mRNA level of TNF-alpha was up-regulated by the cytokine treatment, which points to an autocrine loop augmenting and/or stabilizing the TNF-alpha-MCP-1 pathway. In summary, our data clearly support additional investigations using anti-MCP-1 antibodies in myeloma progression.
authors.affiliation: Tyrolean Cancer Research Institute at the University of Innsbruck, Innsbruck, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Jöhrer
authors.forename: Katrin
authors.initials: K
authors.lastname: Janke
authors.forename: Jens
authors.initials: J
authors.lastname: Krugmann
authors.forename: Michael
authors.initials: M
authors.lastname: Fiegl
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000235:genetics*; D017931:DNA Primers; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018932:Chemokine CCL2; D017931:DNA Primers; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha