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Transendothelial Migration of Myeloma Cells Is Increased by Tumor Necrosis Factor (TNF)- via TNF Receptor 2 and Autocrine Up-Regulation of MCP-1

¹ Tyrolean Cancer Research Institute at the University of Innsbruck; ² Laboratory of Molecular Cytology, Department of Internal Medicine, Division of Hematology and Oncology, University Hospital Innsbruck; and ³ Institute of Pathology, University of Innsbruck, Innsbruck, Austria

ABSTRACT

The proinflammatory cytokine tumor necrosis factor (TNF)- has been shown to facilitate leukocyte transendothelial migration. In multiple myeloma, TNF- is an important factor in the promotion of growth and survival of the malignant cells. Studies have shown that enhanced TNF- levels in myeloma patients correlated with aggressive disease. Therefore, we investigated the effect of recombinant human TNF- 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-, 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- 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-, 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- was up-regulated by the cytokine treatment, which points to an autocrine loop augmenting and/or stabilizing the TNF-–MCP-1 pathway. In summary, our data clearly support additional investigations using anti-MCP-1 antibodies in myeloma progression.

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